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What Do You Know About IP6/IP-6/inositol Hexaphosphate/phytate/phytic Acid?

Discussion in 'Ask For Help or Advice' started by TreasureVibe, Jun 6, 2018.

  1. TreasureVibe

    TreasureVibe Member

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    Hi all. I was wondering, if Ray Peat has ever mentioned IP6. I see it's a subsection here on the Ray Peat forum. Also does anyone know if there are risks related to its use, like anemia? And I've read an anecdotal report before that stated IP6 succesfully chelated cadmium in a person down to zero on his test. Perhaps anyone knows more about IP6's chelating properties? IP6 is also touted in studies as a potent anti-cancer agent, which instead of killing the cancer cells, reverts them back to the normal phenotype. Because of it's natural function to chelate iron, this too aids in cancer because tumors require iron.

    It is touted as a vitamin on its Wikipedia page:

    "The study concludes that: "Given the numerous health benefits, phytates participation in important intracellular biochemical pathways, normal physiological presence in our cells, tissues, plasma, urine, etc., the levels of which fluctuate with intake, epidemiological correlates of phytate deficiency with disease and reversal of those conditions by adequate intake, and safety – all strongly suggest for phytates inclusion as an essential nutrient, perhaps a vitamin."

    Source: Phytic acid - Wikipedia

    Inositol is apparently made in the body as well:

    "It is made naturally in human beings from glucose. Each kidney makes 2g a day; so 4g a day total is made. Other tissues synthesize it too, and the highest concentration is in the brain where it plays an important role making other neurotransmitters, and some steroid hormones bind to their receptors.[3]"

    Source: Inositol - Wikipedia

    However, phytic acid seems to have a possible negative side as well:

    Phytic acid is one of a number of “anti-nutrients” in grains and legumes. For an introduction to this subject, please see this article. Proper preparation of whole grains will neutralize a large portion of these problematic compounds.

    Studies on phytic acid reveal that for some people, the phytic acid in whole grains blocks calcium, zinc, magnesium, iron and copper; others seem immune to these adverse consequences, probably because of favorable gut flora, which in some cases can break down phytic acid. In addition, when animal fats providing vitamins A and D accompany dietary whole grains, the effects of phytic acid are mitigated.

    The author of the following article found that eliminating phytic acid in his diet and the diet of his family helped reverse serious tooth decay; not everyone will need to take such drastic steps. However, proper preparation of whole grains is a good idea for everyone as it is a practice found almost universally among nonindustrialized peoples.

    Source: https://www.westonaprice.org/health-topics/vegetarianism-and-plant-foods/living-with-phytic-acid/

    However, this source states that IP6 is misunderstood by dietitians and the like:

    "Therefore, not only that the key misconceptions about this molecule are nullified, but we have also demonstrated that IP6 is an essential nutrient whose level in plasma and urine fluctuates following deficiency or replenishment (71). In essence, IP6 has many characteristics of a vitamin, contrary to the established and, unfortunately, still existing dogma among nutritionist about its “anti-nutrient” role.
    It is our hope that these apparent conflicting thoughts about the IP6 among biochemists and nutritionists finally will be reconciled."


    Source: https://www.researchgate.net/public...n_Against_Cancer_by_Dietary_IP_6_and_Inositol

    And another source says:

    IP6 is misunderstood
    Unfortunately dietitians have been taught that IP6 is an anti-nutrient, that because of its mineral chelating properties it deprives the body of essential nutrients. Dietitians often fail to distinguish growing children, who have high calcium and iron needs, from adults who begin to accumulate excessive minerals with advancing age. Females experience delayed accumulation of iron because of monthly menstruation and avoid calcium overload by donating this mineral to their offspring during pregnancy and lactation.

    While nutritionists have been taught that IP6 in whole grains and seeds suppress the bioavailability of minerals, when IP6 was added to the diet of mice it did not affect their absorption of iron or calcium. [Journal Nutrition 114: 1192-98, 1984; Journal Nutrition 111: 841-47, 1981] Another study concluded that IP6 has no negative effects on mineral status and that adequate amounts in the diet are “remarkable and must be favorably considered.” [J Trace Element Med Biology15:221-8, 2001]


    Source: Riceplex Global - IP6 Inositol Hexaphosphate

    I found one of the studies referenced:

    https://www.researchgate.net/publication/11515306_Dietary_phytate_and_mineral_bioavailability

    IP6 attaches to heavy metals such as mercury, lead and cadmium, as well as loose iron, copper and calcium. [J Agriculture Food Chemistry 47: 4714-17, 999] IP6 is a selective chelator -- it does not attach to potassium, sodium or magnesium, important electrolyte minerals required for heart rhythm. IP6 does not remove calcium from bones or iron from red blood cells. Once chelated (attached), these excess minerals are excreted via the urinary tract. [Crit Rev Food Sci Nutr. 35:495-508, 1995]

    Also a fascinating article: Inositol Stops Lung Cancer in Cigarette Smokers

    And another: The Overlooked Cancer Cure From Japan - LewRockwell LewRockwell.com

    And another with images: Cancer and IP6 - Conners Clinic

    Good article: IP6 is Highly Effective Alternative Treatment for Cancer

    Populations with diets high in IP6 have low incidences of cancers

    Dr. Shamsuddin's studies have shown that tumor regression takes place in people using 8 grams of IP6 daily for three to four weeks. This is the amount that would be found in 12 ounces of whole kernel corn. One of his studies found that after two weeks the tumors of mice treated three times a week with IP6 were 96 percent smaller than the tumors of mice that did not receive IP6. Populations with diets high in IP6 have lower incidences of cancers of the breast, colon and prostate. Dr. Shamsuddin's laboratory experiments with IP6 have been reproduced and extended by scientists around the world, reconfirming his amazing findings. This study is from Acta Poloniae Pharmaceutica, November through December, 2008.

    IP6 is more than a cancer treatment

    In addition to the anti-cancer benefits of IP6, research is revealing its benefits in treating diabetes, depression, osteoporosis, heart disease, and kidney stones. It has recently been shown to help Parkinson's patients because of its ability to chelate excess iron and thereby reduce oxidative stress that results in neuronal degradation.

    Alot of research on IP6 comes from Dr. Shamsuddin. Here's an interview article about him:

    https://www.healthquestpodcast.com/...-6-my-interview-with-dr-abulkalam-shamsuddin/

    Quote from the article:

    Inositol hexaphosphate (IP(6)) is a naturally occurring carbohydrate, abundantly present in many plant sources and in certain high-fiber diets, such as cereals and legumes. In addition to being found in plants, IP(6) is contained in almost all mammalian cells, although in much smaller amounts, where it is important in regulating vital cellular functions such as signal transduction, cell proliferation, and differentiation. For a long time IP(6) has been recognized as a natural antioxidant. Recently IP(6) has received much attention for its role in cancer prevention and control of experimental tumor growth, progression, and metastasis. In addition, IP(6) possesses other significant benefits for human health, such as the ability to enhance immune system, prevent pathological calcification and kidney stone formation, lower elevated serum cholesterol, and reduce pathological platelet activity. IP(6) is rapidly taken up into cells which further affect signal pathways resulting in cell cycle arrest. A striking anticancer action of IP(6) was demonstrated in different experimental models. In addition to reducing cell proliferation, IP(6) also induces differentiation of malignant cells. Enhanced immunity and antioxidant properties also contribute to tumor cell destruction. Preliminary studies in humans show that IP(6) and inositol, the precursor molecule of IP(6), appear to enhance the anticancer effect of conventional chemotherapy, control cancer metastases, and improve quality of life. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP(6) + inositol holds great promise in our strategies for cancer prevention and therapy. Excerpt (Abstract: Protection against cancer by dietary IP6 and inositol. Nutr Cancer. 2006;55(2):109-25.)

    About Dr. Abulkalam Shamsuddin M.B.B.S., Ph.D.
    Dr Shamsuddin graduated Dhaka Medical College, University of Dhaka in 1972. Following Internship in Massachusetts and Residency training in pathology in Maryland, he was certified by the American Board of Pathology in 1977. In 1980, he received Ph.D. degree from the University of Maryland for his work on colon carcinogenesis. He joined the faculty of the University of Maryland as an Instructor in 1977, and rose through the ranks of Assistant Professor and Associate Professor to become a full Professor in 1988. For his excellence in teaching he received the Best Teacher award from the medical students many times, including the coveted “Golden Apple Award” by the American Medical Students’ Association in 1999.


    Research Interests:
    Dr. Shamsuddin has been studying the process of cancer formation and the prevention of cancer since 1975. His research in the steps of colon cancer formation resulted in the development of a very simple and accurate screening test for colon cancer. This rather inexpensive test detects cancers at a very early stage, and even before they have formed; in other words, it can also detect precancerous polyps and other precancerous lesions and conditions. The test has been in use in China since the early 1990’s often referred to as “Shams’ Test.” He further discovered that the colon cancer marker Gal-GalNAc is a common cancer marker expressed through a similar “field-effect” phenomenon; thus forming the basis for a general cancer screening test such as for cancer of the lungs and breast, and possibly prostate and uterine cervix.

    In mid 1985, Dr. Shamsuddin started his pioneering experiments on the anti-cancer property of inositol and inositol hexaphosphate (IP-6) – natural constituents of cereals and legumes such as rice, corn, beans etc. For the next two decades, he has reconfirmed and expanded his groundbreaking studies to show the efficacy of IP-6 and inositol against different cancers in various experimental models. Dr. Shamsuddin’s book on this “IP6: Nature’s Revolutionary Cancer Fighter” by Kensington Publishing Corporation, New York, 1998, is written for the general public. Aside from these Dr. Shamsuddin has contributed numerous book-chapters and published over 200 scientific papers.


    IP6 is apparently effective when combined in a good ratio with inositol, creating IP3. IP3 is very potent anti-cancer, sources state.

    Here is an informative video on IP6:



    And another one:



    IP6 with inositol is found naturally in every body cell in the human body according to Dr. Shamsuddin. It is disputed wether or not IP6 plays a negative role in radiation therapy for cancer, as IP6 appears to stimulate the NHEJ pathway, according to the following article publishedin 2004, with its discovery of IP6 stimulating NHEJ in 2000:

    Enemy Within

    Dr. Shamsuddin says however, in the following article which was published in 2007 that it is protective and synergetic in radiation therapy for cancer, and that he was inspired to research this as reports from a trial in Croatia which begun in 2001 showed these protective effects during radiation therapy:

    https://www.sciencedaily.com/releases/2007/11/071105083735.htm

    So all in all, its role concerning radiation and radiation therapy for cancer should be further investigated, as it is disputed.

    Also an informative website, by Dr. Shamsuddin himself, I think: http://www.ip-6.net/The_Science.html

    So all in all, IP6 seems to be a very interesting molecule.

    What do you know about IP6?
     
  2. OP
    TreasureVibe

    TreasureVibe Member

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  3. General Orange

    General Orange Member

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    Excuse me, but radiation therapy -> gives you cancer...
    So taking IP6 as an antioxidant while you are being radiated, yes can prevent cancer, but one should not BE radiated in the first place.

    I think a lot of studies like this that try to show "anticancer effects" prevention and treatment of one substance, are to be taken with a grain of salt.
     
  4. OP
    TreasureVibe

    TreasureVibe Member

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    IP-6 and inositol aren't just some random substances, they occur in almost every mammalian cell:

    In addition to being found in plants, IP(6) is contained in almost all mammalian cells, although in much smaller amounts, where it is important in regulating vital cellular functions such as signal transduction, cell proliferation, and differentiation.

    Source: https://www.healthquestpodcast.com/...-6-my-interview-with-dr-abulkalam-shamsuddin/

    It is also appears to be an essential nutrient, with alot of characteristics of a vitamin:

    "Therefore, not only that the key misconceptions about this molecule are nullified, but we have also demonstrated that IP6 is an essential nutrient whose level in plasma and urine fluctuates following deficiency or replenishment (71). In essence, IP6 has many characteristics of a vitamin, contrary to the established and, unfortunately, still existing dogma among nutritionist about its “anti-nutrient” role.
    It is our hope that these apparent conflicting thoughts about the IP6 among biochemists and nutritionists finally will be reconciled."

    Source: https://www.researchgate.net/public...n_Against_Cancer_by_Dietary_IP_6_and_Inositol

    And:

    In humans, IP6 has recently been detected in urine, plasma and other biological fluids; the levels fluctuating with ingestion or deprivation of IP6 or IP6‐rich diet. As IP6 is high in high‐fibre diets, these also may explain, at least in part, the epidemiological observation showing the association of ingesting high‐fibre diets with a lower incidence of certain cancers. Along with safety, the reproducible efficacy of IP6 and inositol in the prevention of cancer in laboratory animals warrant their inclusion in our strategies for cancer prevention and perhaps therapy in humans. Aside from the anticancer action, IP6 and inositol also have numerous other health benefits. All these facts of normal physiological presence of IP6 in our body the level of which fluctuates with intake, association of an IP6‐rich diet with low incidence of several diseases and vice versa, and finally reversal of some of these conditions, at least in part, by IP6supplementation strongly argue in favour of its inclusion as an essential nutrient or perhaps a vitamin.

    Source: https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2621.2002.00620.x

    So its not just some random herb or food, but an actual unrecognized essential nutrient for the human body. There's alot of studies showing its anticancer effects. It was on the list of the American Cancer Society for promising cancer agents according to one source. Only it was removed again apparently, in silence: IP6 and Anti Cancer Properties on the American Cancer Society's Website. CHECK IT OUT. - barryboomer's Question - Cancer Support - WhatNext.com It just never has been followed through. Dr. Shamshuddin's work on it is very intriguing to say the least, and the science is pretty clear. Dr. Peat is not to keen on iron, which IP6 happens to safely chelate, unbound only.

    Ofcourse radiation therapy is bad, but it is an official utilized cancer treatment in oncology, and in that setting, IP6 happened to improve the results, according to some reports. But, as one article stated, it could be bad for radiation therapy results as well. Although that article stated an in vitro discovery. That is why I mentioned it to be something disputed.
     
  5. General Orange

    General Orange Member

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  6. OP
    TreasureVibe

    TreasureVibe Member

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    Most anticancer effects come from IP3 which is made when IP6 and inositol enter the body. The question now is, is IP3 dangerous in supplemental doses? Since it possesses a calcium chelating function, and can mobilize calcium in cells, and pull calcium into cells. Also in the heart. See: Inositol trisphosphate - Wikipedia

    (From other topic)
    [Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane].

    It seems to affect calcium homeostasis of many tissues. The similarity between lindane and inositol (1, 4, 5) phosphate (IP3) suggested that lindane releases Ca2+ from IP3-sensitive intracellular stores in macrophages and myometrial cells. Ca2+ release from reticulum endoplasmic, mitochondria and other Ca2+ stores has been reported in cat kidney cells. Lindane altered energetic metabolism of hepatic mitochondria and the inositol-phosphate synthesis in neuronal cells. However, lindane does not compete with the IP3 receptor. Lindane produces a Ca2+ influx in mice peritoneal macrophage cells responsible for the Ca2+ induced Ca2+ release produced by phospholipase C via IP3 pathway and resulting in a maintained increase of the free cytosolic Ca2+ concentration. Lindane decreased the membrane erythrocyte and cerebral cell concentration of phosphatidyl inositol PI, PIP and PIP2 in rats repetitively exposed to lindane for 3 or 6 months. Lindane induces oxidative stress; it modifies the activity of the scavenger enzymes. This effect is involved in the inhibition of intercellular gap junctions. Modifications of the electrocardiogram (ECG), sinusal rhythm alteration and negative and dysphasic variations of T wave, similar to those produced by hyperkaliemia, have been reported after lindane absorption. During acute lindane poisoning, the activities of serum transaminases (SGOT, SGTP), and lactate deshydrogenase (LDH) increase. Lindane produces histological alterations of cardiac tissues and a cardio-vascular dystrophy (contracture, degenerescence and necrosis) mainly in the left ventricular wall and a hypertrophy of the left ventricle.

    source: [Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane]. - PubMed - NCBI


    What do you think, does the same go for IP3? I am actually thinking of contacting Dr. Vucenik and Dr. Shamsuddin about this.

    Also see: The cardiac IP3 receptor: Uncovering the role of “the other” calcium release channel

    And this: Phytate reduces age-related cardiovascular calcification. - PubMed - NCBI
    and Protection of ischemic heart from reperfusion injury by myo-inositol hexaphosphate, a natural antioxidant. - PubMed - NCBI

    And Epiphany: Modulation of IP3 receptors in Autism – Pancreatitis and Caffeine?

    And: Original article: Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release

    And:

    (Oxytocin is a potent uterine stimulator whose clinical use in labor and delivery is well documented. Researchers have shown that oxytocin's clinical effectiveness is due to the activation of phospholipase C to produce inositol-1,4,5-triphosphate which releases calcium from intracellular stores and stimulates uterine contractions. The activation of the phosphatidylinositol signaling system by calcium agonists is also supported by the work of other researchers).

    Source: Inositol, IP3 and IP6
     
  7. General Orange

    General Orange Member

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  8. OP
    TreasureVibe

    TreasureVibe Member

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    Check this out though:

    (Oxytocin is a potent uterine stimulator whose clinical use in labor and delivery is well documented. Researchers have shown that oxytocin's clinical effectiveness is due to the activation of phospholipase C to produce inositol-1,4,5-triphosphate which releases calcium from intracellular stores and stimulates uterine contractions. The activation of the phosphatidylinositol signaling system by calcium agonists is also supported by the work of other researchers).

    Source: Inositol, IP3 and IP6

    Is Oxytocin known to be cardiotoxic/damaging to the heart?

    This also is kind of confusing, genistein and quercetin lower IP3 in tumors, causing differentiation apoptosis. I thought IP3 was good? Or is this book not correct:

    Principles of Orthomolecularism

    Also very specific and informative:

    Intracellular Signaling Mediators in the Circulatory and Ventilatory Systems

    And this is also significant:

    Huntington's disease[edit]
    Huntington's disease occurs when the cytosolic protein Huntingtin (Htt) has an additional 35 glutamine residues added to its amino terminal region. This modified form of Htt is called Httexp. Httexp makes Type 1 IP3receptors more sensitive to IP3, which leads to the release of too much Ca2+ from the ER. The release of Ca2+ from the ER causes an increase in the cytosolic and mitochondrial concentrations of Ca2+. This increase in Ca2+ is thought to be the cause of GABAergic MSN degradation.[15]

    Source: Inositol trisphosphate - Wikipedia

    Heart disease is a major complication in Huntington's Disease according to Huntington's disease - Wikipedia

    The second greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD.[17]

    Another good source on the specific matter:

    Intracellular Calcium

    The big question now is, which I hope someone can answer, is IP3 in sufficient quantities produced by an IP6 + inositol supplement harmful? And more specifically, is it harmful to the heart?
     
  9. OP
    TreasureVibe

    TreasureVibe Member

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    Amazing, Travis. Any comments on IP3's safety profile, when it gets synthesized in the body after IP6 and Inositol are taken? Can activation or overstimulation of IP3 receptors do harm? Are the amounts of IP3 synthesized big enough to do harm? And is the amount of time it exists significant enough before it dissapears to do harm, if it does harm?
    The interview Dr. Shamsuddin gave was very compelling, now that I've listened to it. He stated that the body loses control over cell differentiation in cancer, and IP6 with Inositol gives this control back, causing differentiation and apoptosis. The interview can be listened to here, it is only 23 minutes long: https://www.healthquestpodcast.com/...-6-my-interview-with-dr-abulkalam-shamsuddin/

    And IP6 has a subsection on it's own here on the RP forum, thats gotta mean something right? In my opinion, if we can determine IP3's safety profile here, and deem it safe, we have an excellent adjuvant in IP6. Here is said official subsection of IP6: IP-6

    IP6's name gives me the idea that it's something synthesized in a lab when hearing it, but in fact it is just a different name for phytate and phytic acid which is found naturally in rice and grain, from which it is extracted. It is not altered after being extracted, as far as I know. Agriculture literature state its existence in crops since 1903*. Dr. Shamsuddin cited how the Danes would still have a high cancer prevalence despite eating a diet high in fiber compared to other populations which also had a high-fiber diet yet had low cancer prevalence. One specialist suggested it could be phytate that is the difference, and Dr. Shamsuddin started researching it, and found out about its anticancer potential. The way of looking at populations reminds of Dr. Peat.

    And if IP6 is a scam, why does it deserve its own subsection here on the Ray Peat forum? To me it looks like you have to believe Dr. Shamsuddin is genuine, and not a crafty salesman who happened to be a scientist too, as alot (but not all) research on IP6 comes from him and his collegues. Wondering why IP6 was never studied in big studies is not relevant to me, as alot of alternative anticancer agents were ignored by the medical establishment. Big pharma is not interested in something that cannot be patented, I suppose.

    *reference to discovery in 1903 source: Inositol Phosphates

    Edit: As I don't want to derail this topic, I suggest moving this discussion to this topic:

    What Do You Know About IP6/IP-6/inositol Hexaphosphate/phytate/phytic Acid?
     
  10. OP
    TreasureVibe

    TreasureVibe Member

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    Amazing, @Travis. Any comments on IP3's safety profile, when it gets synthesized in the body after IP6 and Inositol are taken? Can activation or overstimulation of IP3 receptors do harm? Are the amounts of IP3 synthesized big enough to do harm? And is the amount of time it exists significant enough before it dissapears to do harm, if it does harm?
    The interview Dr. Shamsuddin gave was very compelling, now that I've listened to it. He stated that the body loses control over cell differentiation in cancer, and IP6 with Inositol gives this control back, causing differentiation and apoptosis. The interview can be listened to here, it is only 23 minutes long: https://www.healthquestpodcast.com/...-6-my-interview-with-dr-abulkalam-shamsuddin/

    And IP6 has a subsection on it's own here on the RP forum, thats gotta mean something right? In my opinion, if we can determine IP3's safety profile here, and deem it safe, we have an excellent adjuvant in IP6. Here is said official subsection of IP6: IP-6

    IP6's name gives me the idea that it's something synthesized in a lab when hearing it, but in fact it is just a different name for phytate and phytic acid which is found naturally in rice and grain, from which it is extracted. It is not altered after being extracted, as far as I know. Agriculture literature state its existence in crops since 1903*. Dr. Shamsuddin cited how the Danes would still have a high cancer prevalence despite eating a diet high in fiber compared to other populations which also had a high-fiber diet yet had low cancer prevalence. One specialist suggested it could be phytate that is the difference, and Dr. Shamsuddin started researching it, and found out about its anticancer potential. The way of looking at populations reminds of Dr. Peat.

    And if IP6 is a scam, why does it deserve its own subsection here on the Ray Peat forum? To me it looks like you have to believe Dr. Shamsuddin is genuine, and not a crafty salesman who happened to be a scientist too, as alot (but not all) research on IP6 comes from him and his collegues. Wondering why IP6 was never studied in big studies is not relevant to me, as alot of alternative anticancer agents were ignored by the medical establishment. Big pharma is not interested in something that cannot be patented, I suppose.

    *reference to discovery in 1903 source: Inositol Phosphates


    An Italian study from 2017:

    Nutritional and Acquired Deficiencies in Inositol Bioavailability. Correlations with Metabolic Disorders


    Abstract

    Communities eating a western-like diet, rich in fat, sugar and significantly deprived of fibers, share a relevant increased risk of both metabolic and cancerous diseases. Even more remarkable is that a low-fiber diet lacks some key components—as phytates and inositols—for which a mechanistic link has been clearly established in the pathogenesis of both cancer and metabolic illness. Reduced bioavailability of inositol in living organisms could arise from reduced food supply or from metabolism deregulation. Inositol deregulation has been found in a number of conditions mechanistically and epidemiologically associated to high-glucose diets or altered glucose metabolism. Indeed, high glucose levels hinder inositol availability by increasing its degradation and by inhibiting both myo-Ins biosynthesis and absorption. These underappreciated mechanisms may likely account for acquired, metabolic deficiency in inositol bioavailability.

    Source: Nutritional and Acquired Deficiencies in Inositol Bioavailability. Correlations with Metabolic Disorders
     
  11. Travis

    Travis Member

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    I'd like to know how it works, but it could just be another calcium ionophore or iron chelator. Although inorganic iron does not form nitrosamines in the intestine, it does most likely contribute to cancer through alternative mechanisms. Free iron in the cytosol creates the hydroxyl radical (ȮH⁻) from hydrogen peroxide, which should rightly be converted back into water by either catalase or the selenium-dependent glutathione peroxidase. The hydroxyl radical is the species most effective at initiating a free radical lipid peroxidation chain reaction; this begins with the abstraction of a bis-allylic hydrogen from a non-conjugated diene (i.e. linoleic acid), forming water and a lipid radical (ȮH⁻ + H–L ⟶ H₂O + H–L̇). Oxygen then adds to the lipid radical forming a lipid peroxide, which may then eventually become leukotriene B₄—in the case of arachidonic acid—or a less infamous yet still toxic oxylipid (i.e. 13-hydroxylinolenic acid).Cancer has been correlated with 5-lipoxygenase activity and its leukotriene producs, and ȮH⁻ catalyzes their formation. Ergo: free iron should also be correlated with cancer by increasing oxylipids.

    Stevens, R. "Moderate elevation of body iron level and increased risk of cancer occurrence and death." International journal of cancer (1994)

    'For men and women combined, risk of cancer occurrence in each group relative to the first was 1.0, 0.95, 1.16, 1.38 and 1.81; for mortality the relative risks were 1.0, 0.96, 1.22, 1.29 and 1.73. There is evidence, in this cohort, of elevated cancer risk in those with moderately elevated iron level. This pattern was seen in women as well as in men.' ―Stevens
    You might think that free inositol phosphates could bind extracellular calcium (Ca²⁺), an event which would mostly neutralize its high negative charge allowing it to enter the cell (negatively-charged molecules, such as trypan blue, are generally excluded). Once inside the cell, free inositol phosphates could complex with free iron, reducing ȮH⁻ formation, lipid peroxidation, and cancer. Inositol phosphates could also lower extracellular iron and eventually the body burden, reducing peroxidation while increasing elimination.

    Calcium ionophores also generally tend to inhibit cancer. Although too much intracellular calcium is definitely toxic, not enough increases the activity of the estradiol & androgen receptors (AR) via calmodulin and CBP. Alpha-tocopherol succinate increases intracellular calcium, which increases CREB transcription concomitant with a corresponding decrease in AR transcription (they both compete for the same dimerization partner: CBP). Living cells can sense and respond to calcium, redox status (i.e. NF-κB), heat (ROSE), and even ultraviolet light (cytochrome).
     
  12. Travis

    Travis Member

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    'The ability of myo-inositol polyphosphates to inhibit iron-catalysed hydroxyl radical formation was studied in a hypoxanthine/ xanthine oxidase system. Fe³⁺ present in the assay reagents supported some radical formation, and a standard assay, with 5·μM Fe³⁺ added, was used to investigate the specificity of compounds which could inhibit radical generation. InsP₆ (phytic acid) was able to inhibit radical formation in this assay completely. In this respect it was similar to the effects of the high affinity Fe³⁺ chelator Desferral, and dissimilar to the effects of EDTA which, even at high concentrations, still allowed detectable radical formation to take place. The six isomers of InsP₅ were purified from an alkaline hydrolysate of InsP₆, and they were compared with InsP₆ in this assay. Ins(1,2,3,4,6)P₅ and Ins(l,2,3,4,5)P₅ were similar to InsP₆ in that they caused a complete inhibition of iron-catalysed radical formation at > 30·μM. Ins(1,3,4,5,6)P₅ and Ins(1,2,4,5,6)P₅, however, were markedly less potent than InsP₆, and did not inhibit radical formation completely; even when Ins(1,3,4,5,6)P₅, was added up to 600·μM, significant radical formation was still detected. Thus inositol pentaphosphates that lack #1, #2, & #3 phosphate groups are in this respect qualitatively different from InsP₆ and the other InsP₅ species. Scyllo-Inositol hexakisphosphate was also tested, and although it caused a greater inhibition than Ins(1,3,4,5,6)P₅, it too still allowed detect-able free radical formation even at 600·μM. We conclude that the 1,2,3 (equatorial-axial-equatorial) phosphate grouping in inositol phosphates have a conformation that uniquely provides a specific interaction with iron to inhibit totally its ability to catalyse hydroxyl radical formation; we suggest that a physiological function of inositol phosphates might be to act as a 'safe' binding site for iron during its transport through the cytosol or cellular organelles.'

     
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    TreasureVibe

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    There is signalling by IP3 that Dr. Shamsuddin is aware of, that causes apoptosis. I think this signalling is what makes it such a potent anticancer agent, not even speaking of neutralizing the hydroxyl radical nor iron. The thing is, like you said, IP3 has some actions with IP3 receptors, causing Ca2+ mobilization, which was something seen with Resveratrol too if I am not mistaken. Although in the case of Resveratrol there was no IP3 involved, if I am right. I just get the feeling that people see IP6 under the same category as Resveratrol, perhaps because the people behind Resveratrol worked together with the people behind IP6. But I think that is unfair to the potential IP6 has, and to this date, there has been no literature scrutinizing IP6 in a negative way. If IP6 is fully safe, and the IP3 that gets formed as well, then IP6 bears true significant for better health. I remember reading IP3 was significant when present in tumors, as its activity in there could be used to induce apoptosis. Dr. Shamsuddin wrote 2 books on it where he lays out everything, I should get them.

    The feeling that there is a ''catch'', or that we must atleast be on the look out for such a catch first, is something I do feel. I want to make fully sure that it's safe, and not blindly praise its greatness.

    Our body makes phytase, so is IP6 something the body needs by nature?

    Alot of sources also state that IP6 is able to chelate heavy metals like cadmium and mercury.
     
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    TreasureVibe

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    So IP6 is comparable to alpha-tocopherol succinate? Is the function of IP3 why it's a calcium ionophore? Meaning its safe? When I think of alterations to calcium, I think of potential arrhythmia and the like, but I could be wrong.
     
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    TreasureVibe

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    This is quite amazing. It states nothing about the elusive InsP3 though. I will look for literature about that, thanks for these amazing write-ups, Travis.
     
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    TreasureVibe

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    Here we go:
    IP3 Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer.
    2017

    Abstract
    Calcium ions (Ca2+) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca2+ is shuffled between the cytoplasm and the major Ca2+ stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca2+ signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca2+-release channels in the ER. IP3Rs can transfer Ca2+ to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP3-induced Ca2+ release enhances autophagy flux by providing cytosolic Ca2+ required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mechanistic target of rapamycin inhibition, or drug treatment. Similarly, IP3Rs are able to amplify Ca2+ signals from the lysosomes and, therefore, impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca2+ release through IP3Rs may also be achieved by controlling the sarco/endoplasmic reticulum Ca2+ ATPases Ca2+ pumps of the ER. Considering the complex role of autophagy in cancer development and progression as well as in response to anticancer therapies, it becomes clear that it is important to fully understand the role of the IP3R and its cellular context in this disease. In cancer cells addicted to ER-mitochondrial Ca2+ fueling, IP3R inhibition leads to cancer cell death via mechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP3Rs are the targets of several oncogenes and tumor suppressors and the functional loss of these genes, as occurring in many cancer types, can result in modified Ca2+transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP3R-mediated upregulation of autophagy can protect some cancer cells against natural killer cells-induced killing. The involvement of IP3Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.

    Kania E1, Roest G1, Vervliet T1, Parys JB1, Bultynck G1.
    Author information
    1
    Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Kankerinstituut, KU Leuven, Leuven, Belgium.

    What confuses me is ''Similarly, IP3R-mediated upregulation of autophagy can protect some cancer cells against natural killer cells-induced killing.''
     
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    TreasureVibe

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    Inhibition of Inositol 1, 4, 5-Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics.
    2017

    Singh A1, Chagtoo M1, Tiwari S1, George N2, Chakravarti B1, Khan S3, Lakshmi S4, Godbole MM1.
    Author information
    1
    Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
    2
    Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226017, India.
    3
    Department of Endocrinology, Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India.
    4
    Department of Biochemistry, MS University Vadodara, Vadodara, Gujarat, India.
    Abstract
    Inositol 1,4,5-trisphosphate receptors (IP3 Rs) regulate autophagy in normal cells and are associated with metastasis in cancer cells. In breast cancer, however, the regulation and role of IP3 Rs is not clear. To study this, we used MCF-7 breast cancer cell line and mouse model of breast cancer. Inhibiting IP3 R sub types resulted in compromised bioenergetics both in terms of glucose and mitochondrial metabolism. The siRNA mediated silencing of IP3 R or its blocking by its inhibitors Xestospongin C and 2-Amino-ethoxy diphenyl borate increased cell death and LC3II expression in MCF-7 cells as well as attenuated cellular bioenergetics. The level of Autophagy related gene, Atg5 was found to be up regulated after pharmacological as well as siRNA blocking of IP3 R. The specificity of its role in autophagy was confirmed through specific shRNA knockdown of the Atg5 along with IP3 R inhibitor. Inhibiting as well as silencing of IP3 R receptor also resulted in increase in ROS production which was abolished after pretreatment with N-acetyl cysteine. Its role in autophagy was confirmed through decrease in the levels of LC3 II after pretreatment with IP3 R inhibitor and N acetyl cysteine.Moreover, inhibiting as well as silencing IP3 R-induced cell death in MCF-7 cells was attenuated by autophagic inhibitors (Bafilomycin A1 or 3-Methyladeneine). In mice, blocking of IP3 Rs by 2-Amino-ethoxy diphenyl borate arrested tumor growth. Overall our findings indicate that IP3 R blocking resulted in autophagic cell death in breast cancer cells and provides a role of IP3 Rs in determining the breast cancer cell fate. J. Cell. Biochem. 118: 2333-2346, 2017.

    Inhibition of Inositol 1, 4, 5-Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics. - PubMed - NCBI
     
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    TreasureVibe

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    Tumor suppressive Ca2+ signaling is driven by IP3 receptor fitness
    Geert Bultynck1 and Michelangelo Campanella2,3
    2017
    [​IMG] DOWNLOAD PDF
    Crossref | Pubmed |

    and
    Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M, Pellegrini L, Signorato V, Olivetto F, Pastorino S, Nasu M, Napolitano A, Gaudino G, Morris P, Sakamoto G, Ferris LK, Danese A, Raimondi A, Tacchetti C, Kuchay S, Pass HI, Affar EB, Yang H, Pinton P, Carbone M (2017). BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 546(7659): 549-553.

    | Crossref | Pubmed |

    Intracellular Ca2+ signals critically control a plethora of cellular functions, of which many impact cellular death and/or survival, processes often dysregulated in cancer [1]. In healthy cells, Ca2+ signaling is employed for normal cell physiology and survival functions [2]. Yet, when a cell is exposed to toxic stimuli or suffering from enduring cell stress, like irreparable DNA damage, the Ca2+-signaling toolbox can be rapidly switched from a “pro-survival” modus into a “pro-death” modus, thereby initiating demise pathways [3]. The highly dynamic nature of Ca2+ signaling allows cells to swiftly response to stress and damage, preventing the survival of damaged cells and malignant transformation that eventually results in tumor formation. Alterations in the expression, activity and regulation of Ca2+-transport systems both at the plasma membrane and at organelles like the endoplasmic reticulum (ER) and mitochondria have been implicated in oncogenesis and neoplasia [1][4]. These changes result in aberrant Ca2+-signaling events that could favor resistance to cell death, migration or senescence escape [5].



    Over the last decade, we learnt that tight contacts and functional connections involving Ca2+ exchanges between the ER, the main intracellular Ca2+-storage organelle, and the mitochondria are pivotal for cell-fate decisions [3][6][7][8]. These contact sites contain chaperone-coupled Ca2+-flux systems: the IP3 receptors (IP3Rs) at the ER side and the voltage-dependent anion channels (VDACs) at the mitochondrial outer membrane side [9]. These are controlled/exploited by several cellular factors and regulatory proteins, including oncogenes and tumor suppressors [10][11][12]. Basal Ca2+ fluxes between ER and mitochondria sustain anabolic pathways for mitochondrial metabolism, ensuring proper cell cycle progression [13]. Yet, continued elevated ER-mitochondrial Ca2+ transfers result in loss of mitochondrial membrane integrity and release of apoptogenic factors [14]. Tuned ER-mitochondrial Ca2+ transfer is therefore key to cells’ response to pro-apoptotic stimuli: the failure of which results in cell death resistance, as often observed in cancer cells [15][16]. In fact, the efficacy of chemotherapeutic agents and photodynamic therapy depends on the ability of these agents to elicit ER-mitochondrial Ca2+ exchanges [15]. In the context of apoptosis, previous work proposed unique roles for the type 3 IP3R isoform (IP3R3) [17] and type 1 VDAC isoform (VDAC1) [18] even though other IP3R isoforms can contribute to the initiation of cell death programs [19][20].



    In some cells, the role played by the IP3R3 in pro-apoptotic Ca2+ transfers from ER to mitochondria might relate to its ability to preferentially partner with the VDAC1 complex [18]. Notably, several tumor suppressors and oncogenes located at the ER membranes dodge ER Ca2+ homeostasis and dynamics [10][21]. In general, tumor suppressors increase ER-mitochondrial Ca2+ fluxes, whereas oncogenes suppress ER-mitochondrial Ca2+fluxes. The actions of both tumor suppressors and oncogenes at the ER can involve changes of the steady-state ER Ca2+-filling state through modulation of sarco/endoplasmic reticulum Ca2+ ATPases (SERCA) and/or ER Ca2+-leak channels. For instance, during stress, the tumor suppressor p53 accumulates at the ER and enhances the Ca2+-pump activity SERCA, causing ER Ca2+ overload and the likelihood for pro-apoptotic ER-mitochondrial Ca2+ fluxes [22][23][24]. The anti-apoptotic protein Bcl-2 increases IP3R phosphorylation and its sensitivity to IP3, enhancing the passive Ca2+ leak from the ER, lowering ER Ca2+ levels and so pro-apoptotic ER-mitochondrial Ca2+ fluxes [25]. Several tumor suppressors and oncogenes have been identified as direct regulators of the IP3R, whereby tumor suppressors (like BRCA1, PTEN, PML) and oncogenes (like Bcl-2, PKB/Akt) that respectively promote and suppress the activity of IP3R channels by impacting their gating and consequently their open probability [10][21]. Besides this direct regulation of IP3R gating, it is clear that total IP3R-protein levels impact Ca2+ flux from the ER to the mitochondria and in turn cellular sensitivity to death as well. Insights are now available on IP3R degradation by ER-assisted and 26S proteasomal turnover after cell stimulation and IP3R activation [26]. In such conditions, IP3Rs become ubiquitinated due to recruitment of the erlin1/2 complex and RNF170, an E3 ubiquitin ligase [27][28][29].



    Hitherto, not much was known about the molecular mechanisms impacting basal IP3R turn-over and controlling their steady-state in stressed cells; equally, whether dysregulation of these mechanisms was involved in oncogenesis and/or tumor progression. Nevertheless, it is clear that IP3R levels do impact apoptotic sensitivity [20][30][31][32], and hence cell death and survival proteins were found implicated in regulating IP3R levels [33][34].



    Recent work from Kuchay et al. revealed an unexpected role for the tumor suppressor lipid/protein phosphatase PTEN, an allele frequently lost in cancer [35] and well-known negative regulator of PKB/Akt signaling, stabilizing IP3R channels by protecting them from proteasomal degradation [36] (Fig. 1). This novel function adds to its recently discovered presence at the mitochondria-associated membranes (MAMs), where it contributes to cell death sensitivity by suppressing IP3R3-mediated Ca2+ fluxes [37]. Independently of its catalytic activity, PTEN competes with the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) [38][39] to bind to IP3R3 channels, in particular to a region in the ligand-binding domain. Normal cells that express PTEN will have a low level of the IP3R3/FBXL2-complex formation, preventing the ubiquitination of IP3R3 channels and subsequent targeting to the proteasome. Consistently with previous observations [27][40], activation of cells with agonists increase FBXL2/IP3R3-complex formation and subsequent IP3R3 post-transcriptional regulation via ubiquitination similarly to RNF170-mediated ubiquitination of IP3Rs [27]. Interestingly, FBXL2 activity itself is Ca2+ dependent, but antagonized by calmodulin [41]. Hence, activation of IP3Rs may not only make these channels more susceptible for degradation by increased interaction with FBXL2 but release of Ca2+ itself through IP3Rs may trigger local activation of FBXL2 associated with IP3R3 leading to IP3R3 degradation. Notably, FBXL2 binding to its substrates (like cyclin D3) was found to occur via canonical calmodulin-binding motif thereby preventing ubiquitination. It is nonetheless likely that FBXL2 binding to IP3Rs does not occur by targeting its calmodulin-binding motif even though a role for calmodulin in regulating IP3R3/FBXL2-complex formation may not be ruled out. In any case, access to the degron region in the ligand-binding core of IP3R3 for FBXL2 is facilitated by deletion of the suppressor domain and loss of PTEN is associated with increased FBXL2 binding to IP3R3 and degradation of IP3R3, contributing to the apoptotic resistance of cells [36]. In cancer cells lacking PTEN, FBXL2 knockdown could therefore restore IP3R3 levels and apoptotic sensitivity.



    [​IMG]
    FIGURE 1: IP3R3 channels are targets for ubiquitination and deubiquitylation enzymes, whose activities are deregulated in cancer cells, thereby impacting IP3R3 stability and ultimately cell death sensitivity. (A) IP3Rs, located at the ER-mitochondrial interface, here particularly IP3R3, promote ER-mitochondrial Ca2+ fluxes, thereby enabling adequate cell death sensitivity in healthy cells undergoing genotoxic stress and cell damage, an important feature that prevents oncogenesis. The levels of IP3R3 channels are critical for this process and are dynamically regulated via ubiquitination. BAP1, a tumor suppressor with deubiquitylation enzyme activities and frequently mutated in cancers including mesothelioma, deubiquitylates IP3R3, preventing its proteasomal degradation and resulting in IP3R3 stabilization. In contrast, FBXL2, an F-Box protein with ubiquitin ligase activity, ubiquitinates IP3R3, directing it for proteasomal degradation and resulting in a decline in IP3R3 levels. Importantly, PTEN, another tumor suppressor that antagonizes Akt signaling and frequently mutated in a variety of cancers including prostate cancer, competes with FBXL2 for IP3R3 binding and thus antagonizes FBXL2-mediated ubiquitination of IP3R3, stabilizing IP3R3. In healthy cells, it is anticipated that the balance between deubiquitylation and ubiquitination of IP3R3 channels is favored towards deubiquitylated IP3R3, enabling sufficient IP3R3 channels to sustain adequate ER-mitochondrial Ca2+ fluxes in cells undergoing genotoxic stress and cell damage to engage cell death and eradicate pre-malignant cells with DNA damage. (B) Several cancer types display chromosomal aberrations with defects in the expression of several tumor suppressors, including a reduction in BAP1 levels and a loss in PTEN expression. As a consequence, both alterations will favor IP3R3 ubiquitination and degradation, since reduced BAP1 levels will lead to reduced deubiquitylation of IP3Rs and loss of PTEN will enable FBXL2 to mediate IP3R3 ubiquitination. As a consequence, the balance between ubiquitination and deubiquitylation of IP3R3s will shift towards ubiquitinated IP3R3, impairing ER-mitochondrial Ca2+fluxes that are needed to engage cell death programs in response to genotoxic stress and cell damage. As such, cells will be able to withstand this cellular stress, resulting in their survival and proliferation despite accumulated DNA damage. This phenomenon is an early event in oncogenesis, enabling malignant cell formation and tumoral behavior.



    Notably, authors show that by mutating the degron region in the ligand-binding domain in IP3R3 the FBXL2 binding and IP3R3 degradation were both prevented. Using a knockin approach in which wild-type IP3R3 was altered into a non-degradable IP3R3 mutant version (IP3R3Q550A/F553A/R554A), the authors could restore the rise of Ca2+ induced by photodynamic therapy and apoptosis in PTEN-negative cancer cells. This correlation was eloquently observed in human tumor samples beyond the convincing in vivo xenograft models, in which tumor cells expressing a non-degradable IP3R3 version or treated with geranylgeranyltransferase inhibitor (that prevents FBXL2 accumulation at ER membranes and activity, which depends on its geranylgeranylation [42]) were greatly sensitized towards photodynamic therapy compared to tumor cells expressing wild-type (degradable) IP3R3 or untreated tumors.



    It is important to note that FBXL2 has been previously implicated in cancer, but rather acting via the suppression of cell cycle progression and proliferation, as observed in lung tumors [43], leukemic cells [44], gastric cancer cells [45], and prevalently of tumor suppressive nature. Instead, in this work, the effects of FBXL2 on IP3R3 are tumor promoting by increasing IP3R3 degradation and making the cells more resistant to cell death [36]. These effects are neutralized by PTEN, which prevents FBLX2 binding to IP3R3 channels. This interference by PTEN is likely selective for IP3R3 and not for other FBXL2 targets regulating the cell cycle. Nevertheless, the anti-cancer properties of FBXL2 activators like the small molecule BC-1258 [46] will be adversely impacted by FBXL2-mediated IP3R3 degradation, likely limiting their application to PTEN-positive cancers. Vice versa, the previously discovered tumor suppressive properties of FBXL2 in cancer might be further boosted if FBXL2 could be selectively/subcellularly activated to pro-mote its cell-cycle targets while shielding IP3R3 for degradation.



    In a separate study, Bononi et al. revealed a novel deubiquitylating enzyme that actually counteracts the level of IP3R3 ubiquitination, namely BRCA-associated protein 1 (BAP1) [47] (Fig. 1). BAP1 is a potent tumor suppressor, which protects against environmental stress and damage [48]. Loss of one BAP1 allele either inherited or acquired during life has been associated with environmental stress-induced carcinogenesis, like UV light for uveal melanoma and asbestos for mesothelioma. Germline mutations in BAP1 resulting in aberrant/loss of BAP1 expression were associated with a high incidence of familial mesothelioma and uveal melanoma, while somatic mutations in BAP1 were found in sporadic mesotheliomas [49]. Germline mutations in BAP1 greatly enhanced the sensitivity of mice to develop mesothelioma when exposed to asbestos [50]. Recently, it has been shown in patient fibroblasts that loss of BAP1 displayed a metabolic rewiring towards aerobic glycolysis and reduced mitochondrial respiration associated with malignancy and carcinogenesis [51]. BAP1 was therefore identified as a novel IP3R3-interacting protein that impacts its post-translational modification. BAP1 causes IP3R3 stabilization and prevents the channel to be degraded by the proteasome. Loss of only 1 allele in BAP1 is sufficient to protect cells from undergoing apoptotic cell death via suppressed Ca2+ release triggered by apoptotic stimuli like H2O2. An effect operated via the IP3R3 degradation due to a decreased BAP1-mediated deubiquitylation of IP3R3. As a consequence, exposure of cells being BAP1+/- to DNA-damaging conditions will result in a higher percentage of cells surviving despite having damaged DNA. Such cells bearing genomic aberrations are at high risk for neoplastic behavior and oncogenesis, resulting in malignant cell growth and tumor formation. However, restoring IP3R3 in these cells could be an attractive strategy to reinstate cell death sensitivity of BAP1+/- cells.



    Based on these recent developments, it will be therefore important to examine the interplay between BAP1 and FBXL2. It is indeed not clear whether the increased IP3R3 ubiquitination observed when BAP1 levels are declined is mediated through FBXL2 and whether lack of BAP1 results in increased FBXL2 association with IP3R3 channels. In any case, by inhibiting FBXL2’s action on IP3R3 without inhibiting its action on cell cycle targets could be an attractive avenue to restore IP3R3 levels in these cancers. Another strategy can be boosting ER Ca2+-store loading in tumor cells by activating the SERCA pumps, thereby increasing the likelihood for ER-mitochondrial Ca2+ fluxes and restoring cellular sensitivity to apoptosis [22][52]. Tumor-selective SERCA modulation is challenging but not impossible though, as evidenced by the ability to locally release thapsigargin in the vicinity of pancreatic tumor cells using peptide-coupled prodrugs that are enzymatically cleaved by prostate-specific factors [53]. SERCA-activating approaches may be based on p53, recently proposed to activate SERCA activity in response to chemotherapy [22][23][24], although p53 is very frequently mutated in cancer. In wild-type p53 tumors, direct p53 activators might be of use. Other solace may come from SERCA-activating small molecules like CDN1163 [54], provided these agents can be delivered to tumor cells while sparing healthy cells [52].



    These recent papers highlight that deregulation of IP3R3 ubiquitination homeostasis not only impacts death and survival of cells but also contributes to the oncogenic behavior of cells with dysfunctional tumor suppressors by either (i) lacking PTEN [36] or by (ii) displaying deficiencies in BAP1 [47]. They underpin the emerging role of altered Ca2+ signaling at the MAM level as a key event in apoptosis resistance that contributes early events associated with oncogenesis and tumor formation. Challenging will be the translation of these insights into anti-cancer therapies for which not only tumor-selective applications will be required but also further understanding in the selective targeting at the level of the IP3R3.


    Source: Tumor suppressive Ca2+ signaling is driven by IP3 receptor fitness
     
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    TreasureVibe

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    IP3 Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer
    Elzbieta Kania,1 Gemma Roest,1 Tim Vervliet,1 Jan B. Parys,1,* and Geert Bultynck1,*
    Author information ► Article notes ► Copyright and License information ► Disclaimer
    This article has been cited by other articles in PMC.
    2017
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    Abstract
    Calcium ions (Ca2+) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca2+ is shuffled between the cytoplasm and the major Ca2+ stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca2+ signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca2+-release channels in the ER. IP3Rs can transfer Ca2+ to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP3-induced Ca2+ release enhances autophagy flux by providing cytosolic Ca2+ required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mechanistic target of rapamycin inhibition, or drug treatment. Similarly, IP3Rs are able to amplify Ca2+ signals from the lysosomes and, therefore, impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca2+ release through IP3Rs may also be achieved by controlling the sarco/endoplasmic reticulum Ca2+ ATPases Ca2+ pumps of the ER. Considering the complex role of autophagy in cancer development and progression as well as in response to anticancer therapies, it becomes clear that it is important to fully understand the role of the IP3R and its cellular context in this disease. In cancer cells addicted to ER–mitochondrial Ca2+ fueling, IP3R inhibition leads to cancer cell death viamechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP3Rs are the targets of several oncogenes and tumor suppressors and the functional loss of these genes, as occurring in many cancer types, can result in modified Ca2+ transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP3R-mediated upregulation of autophagy can protect some cancer cells against natural killer cells-induced killing. The involvement of IP3Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.

    Source: IP3 Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer
     
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    Role of Inositol Triphosphate Receptor in Cancer and Its Targeting Through Autophagy
    2015


    Abstract

    The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are a family of Ca2+ release channels localized predominately in the endoplasmic reticulum of all cell types. They function to release Ca2+ into the cytoplasm in response to IP3 produced by diverse stimuli, generating complex local and global Ca2+ signals that regulate numerous cell physiological processes ranging from gene transcription and secretion to learning and memory. These receptors regulate the transfer of Ca2+ from ER to mitochondria via transport protein on mitochondrial membrane which regulates cellular bioenergetics. IP3R/Ca2+ release channel is most ubiquitously expressed which can enhance or inhibits autophagic process to induce cell death of cancer cells. There are evidences linking calcium homeostasis to the regulation of apoptotic and autophagic cell deaths. The present chapter will focus on the inositol triphosphate receptor and how this can be used as a tool to target cancer through autophagy.

    Role of Inositol Triphosphate Receptor in Cancer and Its Targeting Through Autophagy | Request PDF. Available from: https://www.researchgate.net/public...in_Cancer_and_Its_Targeting_Through_Autophagy [accessed Jun 08 2018].

    Source: https://www.researchgate.net/public...in_Cancer_and_Its_Targeting_Through_Autophagy
     
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