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Estrogen As The Main Cause Of Cancer And Its Progression

Discussion in 'Scientific Studies' started by haidut, Feb 21, 2018.

  1. haidut

    haidut Member

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    I think many of the forum users here know about the infamous study that generated a lot of controversy on "scientific" forums like Reddit. It basically showed that the Warburg Effect (overproduction of lactate) is not just an effect but a direct cause of cancer. So, as the top rated comment on the study's Reddit discussion said the debate of whether cancer is metabolic or genetic disease is now probably over.
    The Warburg Effect drives oncogenesis: researchers at Lawrence Berkeley National Lab and in Japan show cancer really does have a sweet tooth • r/science
    The Warburg Effect drives oncogenesis: researchers at Lawrence Berkeley National Lab and in Japan show cancer really does have a sweet tooth • r/science
    "...There's been a long running debate over whether or not the well known Warburg Effect is a result of genetic transformation of cells into a malignant state or whether the Warburg Effect is a key driver of the transition. The debate may now be beginning to be over."

    So, going forward I will start referring to the Warburg Effect as the Warburg Cycle to signify its role as a cause of lactate overproduction, which causes further hypoxia and further lactate production. But if the WC is the direct driver of cancer, what is the non-genetic cause of the WC causing it to appear in the first place?? Well, mainstream medicine likes to claim that injury of some sort or infection are involved. The first part of this statement is actually quite accurate when applied to environmental toxins like BPA or radiation (both ionizing and non-ionizing). However, those connections are immediately dismissed by most doctors as "spurious" for lack of "conclusive" evidence. The infectious cause of cancer continues to be researched but so far has not produced very convincing results unless there is concurrent immunosuppression.
    So, aside from toxins and infection (which account for the minority of cancers) what else could be driving the WC? This study below does a very thorough job of exposing estrogen as a signal that affects every step of the cancer metabolism, promoting it in every aspect imaginable - stabilizing HIF, inhibiting PDH, enhancing PDK, promoting fatty acid oxidation, increase NADH (and thus lowering NAD/NADH ratio and PDH activity), and inhibiting glucose oxidation. Perhaps just as importantly, it states that "cancer" cells have intact mitochondrial function, which countless other studies have shown as well, Peat has repeatedly emphasized, and I have mentioned in so many of my posts and podcasts with Danny Roddy. So, the metabolic defect which makes them become "cancerous" is likely entirely functional, and as such, fully reversible! While antiestrogen therapies would be a great preventative tactic, reversing a cancerous metabolism of already established tumor would likely need a combination of the former and inhibition of FAO in order to "push" the cells back into metabolic normality. Progesterone, androgens (preferably 5-AR derived in order to better oppose estrogen), aspirin, niacinamide, thyroid, anti-serotonin chemicals, vitamin B1, dietary SFA, etc would form the basis in such therapy. Of course, this is no news and the same list of substances can be seen in pretty much any of Peat's articles, but in light of the study below that list makes especially good sense.
    @Travis, @Koveras, @Kyle M, @aguilaroja, @Suikerbuik, @Drareg, @Such_Saturation

    Regulation of glycolysis and the Warburg effect by estrogen-related receptors. - PubMed - NCBI
    "...Metabolic switch to aerobic glycolysis in cancer cells is driven primarily by oncogenic signaling pathways involving kinases such as PI3K and Akt, and transcription factors, most notably, hypoxia-inducible factor (HIF) and Myc (59). Either due to an intratumoral hypoxic microenvironment or as a result of genetic defects, HIF is stabilized in cancer cells. HIF directly binds to and activates transcription of glucose transporter and nearly every gene in the glycolytic pathway (10). Meanwhile, HIF upregulates pyruvate dehydrogenase kinase (PDK) 1, which in turn inhibits the PDH complex, a rate-limiting enzyme for glucose oxidation (1113). Therefore, HIF induces a dramatic reprogramming of cancer cell metabolism involving increased glucose uptake and glycolytic flux, and concomitantly decreased glucose oxidation. Many genes encoding glycolytic enzymes are also direct targets of Myc (14). Myc enhances glycolysis without hypoxia. Furthermore, HIF and Myc, both of which are highly expressed in most tumor types, collaborate to direct a transition to glycolytic metabolism during cell proliferation or tumorigenesis (7).

    "...We recently identified the estrogen-related receptors (ERRs) α, β, and γ (NR3B1, 2, and 3) as coactivating factors of HIF (15). ERRs interact with HIF and enhance HIF-induced glycolytic and angiogenic gene expression under hypoxia (15). ERRs are orphan nuclear receptors that are constitutively active without exogenously added ligands, although their transcription activity is further augmented in the presence of coactivator proteins, in particular the PGC-1 family of coregulatory proteins (16,17). Expressed mostly in tissues with high metabolic demands, ERRs play a predominant role in orchestrating mitochondrial biogenesis and cellular energy metabolism such as oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle, fatty acid oxidation (FAO), and ATP synthesis (16). ERRs directly activate transcription of numerous genes involved in mitochondrial oxidative metabolism. Consistently, engineered ablation of ERRα or ERRγ in mice results in impaired mitochondrial biogenesis and oxidative capacity in heart muscle, fat cells, and macrophages (16)."

    "...Glucose and fatty acids compete for their oxidation, which is described as the Randle cycle (18). While promoting FAO, ERRs inhibit glucose oxidation by upregulating PDK4 (1921). Like PDK1, PDK4 inactivates PDH and decreases glucose carbon flux into TCA. The similar activity of ERRs and HIF in blocking glucose oxidation and their collaboration in hypoxic gene transcription prompted us to examine whether ERRs might also directly regulate glycolysis. Accumulating evidence implicates ERRs in the glycolysis pathway. Genome-wide chromatin immunoprecipitation (ChIP)-based binding studies in mouse and human cells revealed the occupancy of ERRs not only at genes of oxidative metabolism but also at glycolytic gene loci (2224). Moreover, the Drosophila ortholog of ERR, dERR, is required for induction of glycolysis to support cell proliferation during mid-embryonic development (25). The fly Pfk glycolytic gene is a direct transcriptional target of dERR, and most glycolytic genes and lactate levels are significantly downregulated in dERR mutants (25)."

    "...ERRα has been identified as a negative prognosticator in breast and other cancers, and its expression generally correlates with advanced tumor stage and histological grading (26,27). ERRγ mRNA was found to be overexpressed in 75% of the breast tumors compared to normal mammary epithelial cells, and its overexpression is associated with estrogen receptor (ER)-positive status, and thus, anti-estrogen sensitivity and a favorable prognosis (26). Depletion of ERRα in the MDA-MB-231 breast cancer cells decreases the growth rate of tumor xenografts (28). Given that altered metabolism is vital for tumor growth and that ERRs are global metabolic regulators, we investigated whether ERRs might regulate glucose metabolism in cancer. In the present study, we confirmed that ERRs bind to promoters of many glycolytic genes and activate their expression through the ERR-binding sites. ERRs interact and synergize with Myc in activation of glycolytic genes. Overexpression of ERRs increases glycolytic gene expression and lactate production; conversely, depletion of ERRs in cancer cells downregulates the aerobic glycolytic phenotype and cell growth. Collectively, these findings suggest that ERRs promote glycolysis, and together with well-established glycolysis-driving transcription factors Myc and HIF, contribute to the metabolic transformation of cancer cells."

    "...Increased glucose consumption and glycolysis facilitate cell proliferation by meeting both bioenergetic and anabolic needs of dividing cells. As depletion of ERRs reduced glycolysis, it was anticipated that cell growth would be affected as well. MCF7 cells depleted of ERRγ demonstrated modestly yet significantly reduced growth rate compared to control cells (Fig. 6E), but depletion of ERRα did not have a clear effect (Fig. 6E). In T47D cells, depletion of either ERRα or ERRγ significantly impaired cell growth (Fig. 6F). Similar phenomenon was also observed in MDA-MB-435 cells (Fig. S3B). These results suggest that ERRs are modulators of cancer cell growth."

    "...According to the Randle cycle (18), oxidation of glucose and fatty acids is reciprocally inhibitory. FAO produces acetyl-CoA, which enters the TCA cycle to generate NADH. Both acetyl-CoA and NADH can inhibit the PDH complex, uncoupling glycolysis from subsequent oxidation (18). ERRs are known to promote oxidative metabolism of fatty acids by activating genes critical for mitochondrial uptake and β-oxidation of fatty acids (16). By enhancing FAO and inhibiting glucose oxidation through upregulation of PDK4, ERRs may be part of the regulatory mechanism underlying the Randle cycle and metabolic substrate selectivity. However, the two FAO products do not directly inhibit glycolysis. Consequently, unlike glucose oxidation, glycolysis is compatible with FAO. Indeed, inhibition of glucose oxidation by FAO should further diverts pyruvate to lactate, and hence enhance aerobic glycolysis. Therefore, stimulation of glycolysis by ERRs does not necessarily conflict with ERRs’ existing role in FAO. This metabolic control is reminiscent of AMPK, a key kinase in energy metabolism. AMPK orchestrates cellular energy conservation by activating catabolic pathways, including glucose uptake, glycolysis, and FAO (30)."

    "...Cancer cells generally retain intact mitochondrial function. While they exhibit a shift from glucose oxidation to glycolysis, cancer cells may have varying degrees of oxidative metabolism, probably depending availability of oxygen and fuel types (e.g. glutamine and fatty acids) (31). Oxidative metabolism also feeds the energetic and anabolic demands of dividing cells: the TCA cycle supplies important intermediates for lipid and amino acid biosynthesis, and OXPHOS efficiently generates ATP (2,9). ERRs are master regulators of mitochondrial oxidative metabolism including the TCA cycle and OXPHOS (16). The finding that ERRs also promote glycolysis suggests that the two main metabolic pathways can be integrated under the control of a common transcription factor, which may offer growth advantages to cancer cells. Although different ERR members may function differently (e.g. depending on cell types) (32), ERR-expressing cancer cells may rely on different metabolic programs to adapt to nutrient supply, oxygen availability, and energy demand. In this regard, Myc stimulates aerobic glycolysis as well as mitochondrial respiration and glutaminolysis (33,34). Anti-glycolysis treatment as monotherapy so far only results in a limited effect on tumorigenesis (8), which might be attributed to tumor’s ability to switch from glucose dependence to a reliance on oxidative metabolism of other fuels."
     
  2. Such_Saturation

    Such_Saturation Member

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    This is good, once the anti-carb fad ends we will be basically left with widespread Peatism :lol:
     
  3. Travis

    Travis Member

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    I was thinking of why this observed increase in lactic acid, or this uncoupling of respiration, should increase proliferation. That is to say: what what physical forces account for mitosis? I think I've already pinpointed one of them—polyamines, which interact with DNA directly at CpG islands—but there must be others.

    I think the shift away from respiration has the intention of diverting two carbon units—which would normally escape the body as CO₂—towards fatty acid synthesis. Fatty acids aren't needed only for adipose tissue, but are indispensable to the dividing cell because its membrane literally needs to double in mass. So for a cell to divide
    it needs polyamines to increase the rate of DNA transcription concomitant with an increase in fatty acid synthesis, a process which the uncoupling of mitochondria facilitates through the preservation of Kreb's Cycle two-carbon units (acetyl–CoA)—incorporating them into a growing lipid chain.

    Coupled with fatty acid synthesis is the enzyme stearoyl–CoA desaturase: Found on the endoplasmic reticulum, this enzyme desaturates this newly-formed stearic acid to oleic acid; this double bond increases membrane fluidity, a property which has long been observed in mitotic cells. The double bond also increases the volume—or lowers the density—of the dividing cell membrane, due both to steric effects and the increased molecular kinetic energy inherent to all unsaturated fatty acids (relative to their respective isocarbonic saturated analogues). So both the increase in fatty acid synthesis coupled with thier desaturation serves to both increase the fluidity and size of the cell membrane, preparing it for mitosis. It should then be no surprise that stearoyl–CoA desaturase is consistently found upregulated in cancer:

    ➞ Igal, R.A. "Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer." Carcinogenesis (2010)

    'Before cell division, cells must double their membrane content in order to maintain the size/surface ratio in daughter cells. Thus, external factors that induce cell proliferation, such as nutrient availability and growth factors, trigger the synthesis of membrane lipid components. Specifically, the synthesis of phospholipids and cholesterol, the two major components in mammalian cell membranes, is coordinately regulated with cell cycle. Cells must then expand the amount of lipids with a distribution of fatty acid species that is appropriate for maintaining the functions of dividing cells.' ―Igal

    'As reported by Chajes, serum levels of fatty acids may have certain predictive value for breast cancer in premenopausal women. These investigators found that when fatty acid composition was determined in sera of women who developed breast cancer and age-matched controls, unbalanced levels of stearic acid (low) and oleic acid (high) appeared positively correlated to cancer but not to metastasis.' ―Igal

    'Studies from our laboratory revealed the presence of a strong functional association of SCD1 activity with membrane lipid synthesis in neoplastic cells. In these cells, a several fold overexpression of SCD1 is the cause of the marked enrichment of phospholipids with MUFA.' ―Igal

    'Interestingly, it was also found that the observed reduction in SCD1 was parallel to a decrease in FAS, the main substrate provider for the SCD1 reaction, suggesting a coordinated repression of fatty acid synthesis and desaturation when cells slow down or stop proliferation.' ―Igal


    'This observation suggests that the parallel activation of glycolysis and fatty acid synthesis in cancer is tightly coupled to the conversion of SFA into MUFA and also implies that MUFA are major end products of glucose metabolism in cancer cells.' ―Igal

    'In this study, it was observed that the expression and activity of SCD1 were dramatically reduced when the senescent state in normal fibroblasts was reached.' ―Igal

    'As described earlier, cancer cells continuously synthesize SFA and MUFA by a tandem of reactions involving adenosine triphosphatecitrate lyase, ACC, FAS and SCD1.' ―Igal

    'Also, a recent prospective study conducted in a French cohort reported a significant link between unbalanced levels of SFA and MUFA in prediagnostic sera and breast cancer risk.' ―Igal

    'Similar results were obtained in cancer cells in which SCD1 activity was acutely blocked with a specific small molecule inhibitor of the desaturase, adding more definitive proof to the concept that SCD1 controls the overall process of lipogenesis in cancer cells.' ―Igal

    'Furthermore, in a recent study designed to identify new cancer targets, a siRNA library against 3700 genes was screened in several cancer cells in search for suitable targets for inducing cytotoxicity and cell death. Remarkably, SCD1 was one of the three main targets identified in the screening, confirming the observations that SCD1 is a crucial factor for cancer cell survival' ―Igal

    This is an important enzyme that can be upregulated by molecules such as prostaglandins, androgens, insulin, insulin-like growth factor, and prolactin—and inhibited by vitamin D and thyroid hormone. It is also controlled by the lipids themselves in a negative–positive feedback manner, as if it were attempting to maintain a steady-state unsaturation index by increasing its activity in the presence of saturated fatty acids while being inhibited by polyunsaturated fatty acids.

    ➞ Mauvoisin, D. "Hormonal and nutritional regulation of SCD1 gene expression." Biochimie (2011)

    'Another powerful inhibitor of SCD1 is the thyroid hormone T₃. Waters and Ntambi showed that injection of T₃ in mice strongly represses hepatic SCD1 mRNA levels. Moreover a study performed in HepG2 cells showed that SCD1 transcriptional repression by T₃ is dependent on the binding of the T₃ receptor-α on a T₃ response element located on SCD1 promoter.' ―Mauvoisin

    'PPAR-γ also targets SCD1 in adipose tissue and a human study supports the role of PPAR-γ in SCD1 regulation.' ―Mauvoisin

    But is this enough to explain mitosis, physically? Probably not, since any additional fatty acids would only be expected to crowd-out the intracellular space and trans-
    forms the cell membrane's lipid bilayer into a lipid trilayer—then tetralayer ⟶ pentalayer ⟶ et.c. There needs to be a slight increase of intracellular pressure to counter that of the extracellular space, restraining the cell—a force an efficient cancer cell could have reduced beforehand using a matrix metalloproteinase enzyme to dissolve collagen. This has actually been studied, and it has been found to occur. It's easy to imagine this increase in pressure could occur through a shift in the Na⁺/K⁺ ratio but Anne Dupre's data indicate that this effect is mediated through a reduction in membrane permeability—perhaps allowing the entropy of glycolysis to inflate the cell:

    ➞ Dupre, A. "Osmotic properties of Ehrlich ascites tumor cells during the cell cycle." Journal of cellular physiology (1978)

    'In this paper, we will show that synchronized ascites tumor cells change their membrane permeability to water during the cell cycle.' ―Dupre

    'Permeability to water is highest at the initiation of S [synthesis phase] and progressively decreases to its lowest value during mitosis.' ―Dupre


    cycle.png

    'Cell volume varies linearly with the reciprocal of the osmotic concentration of the solution (Boyle-van’t Hoff law);' ―Dupre

    'The decrease in ΔH may indicate a change in membrane fluidity at this time.' ―Dupre

    'For a given surface area, temperature, and osmotic gradient, membrane permeability to water decreases during the mitotic phase. The drop in H₂O permeability may be associated with increased thickness or mass/surface area of the membrane. This raises a question about whether new membrane components are synthesized and inserted continuously during the cell cycle or only during certain stages.' ―Dupre

    So how is this achieved? do permeability-reducing proteins exists? Could they perhaps be 'aquaporin blockers' of some type produced by estradiol? Not certain; cancer cell osmosis is a relatively esoteric filed so I don't think think there are any quick answers to this one. But what is certain is that estradiol does upregulate two membrane proteins which could have relevance, as determined though a screening of ~20,000 human genes.. . .


    estradiol.png click to embiggen
     
  4. OP
    haidut

    haidut Member

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    Thanks, very informative. What about something simpler - lactic acid being a signal that "life is hard right now" and maintaining a higher organism is untenable. So, cells sensing lactic acid dismantle their bulky OXPHOS apparatus and retain glycolysis as the main energy factor since it is "cheaper" to maintain. It is basically a cell quorum thing, a group decision on what to do given the environmental conditions. Once the quorum is sufficiently loud that "life is hard right now", the process is akin to the organism reverting back to a more primitive life form and basically saying "apparently we can't have 37 trillion highly differentiated cells, so we are going to compensate by having 10 x 37 trillion very primitive, functionless, and low-maintenance cells". I posted some studies about that before.
    Warbug Effect Revisited - Glycolysis Is "cheaper" For Dividing Cells
    Warbug Effect Revisited - Glycolysis Is "cheaper" For Dividing Cells
    Collective Cellular Communication Key For Health And Disease (cancer)
     
  5. ddjd

    ddjd Member

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    Doesn't the increase in rates of cancer since mid 20th century, completely correlate with the start of widespread use of plastics, synthetic estrogens, xenoestrogens etc. Finally we've got scientific research to prove what we've all pretty much strongly suspected for the last few decades. Makes complete sense.
     
  6. OP
    haidut

    haidut Member

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    Yes, it does. However, the mainstream view is still that cancer is due to mutations and above all chance - i.e. "bad luck". Ask any doctor if cancer is genetic or environmental/metabolic and you will see how defensive and sometimes vicious they become.
     
  7. Vinero

    Vinero Member

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    Don't forget the heavy marketing of the vegetable oils of the seed oil industry. Before the mid 20th century most people consumed animal fats such as lard, tallow, and butter. Most animal fats such as chicken and pork were probably more saturated back then.
     
  8. ddjd

    ddjd Member

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    My girlfriends a doctor. She won't even agree with me on aspirin and still takes ibruprofen. I just avoid talking about it now, too frustrating! completely indoctrinated
     
  9. Suikerbuik

    Suikerbuik Member

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  10. Kyle M

    Kyle M Member

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    bulk water, which is increased by estrogen
     
  11. Travis

    Travis Member

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    The Dupre article has measured this as well, and they had found an increase:

    osmosis.png click to embiggen: Graph depicting an increase in cellular bulk water approaching mitosis

    However! Bulk water is generally considered—by Ling, Pollack, and nearly everyone else—to represent a low-entropy, ordered, and almost 'supercooled' state. As such, bulk water would then occupy less volume than the osmotically-active water having more translational kinetic energy. Since bulk water adsorbs onto proteins—certainly not onto lipids—then this increase in bulk water could perhaps rightly be viewed as a side-effect of increased protein synthesis, which you'd expect for a cell approaching mitosis. The affinity of water for the hydrophilic areas of proteins is such that you might expect the 'bulk water vs time' curve above to be nearly superimposable over the 'protein density vs time' curve.

    The decreased membrane permeability coupled with an increased entropy of glycolysis slowly expand the cell like a balloon. The mitochondrial uncoupling serves primarily to 'fix carbon,' or to transform the two carbon units that'd otherwise escape as CO₂ into growing lipid chains—also obligatory for mitosis to occur, as phospholipids are surely needed to nearly double the cell membrane volume.

    Estrogen certainly does upregulate translation enzymes (and asparagine synthetase 12.1× for some odd reason):

    estradiol.png

    And the classic tumor-associated transcription factor c-fos, which has downstream transcription effects of its own. This is thought to occur through a cytosolic estrogen receptor—the G protein-coupled receptor #30—located on the endoplasmic reticulum:

    c-fos.png
     
  12. Kyle M

    Kyle M Member

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    My take on it is that bulk water is simply cellular water that isn't adsorbed to proteins. The destabilizing effect this would have on cellular structure is, to my mind, a necessary part of conducting cellular cleavage into daughter cells. A fully structured cell is too stable to split into two.

    The same anti-stability drivers (like estrogen) that allow for (or force) cleavage, may by the same physical processes destabilize the cytoplasm and mitochondria such that they don't produce or transfer energy properly. As the ratio of bulk to structured water increases, the cell falls into a trap of decreased energy production and increased rate of division, which becomes self-perpetuating as the energy needed to collect the water back onto surface proteins with proper ATP, CO2, and ionic forces, is not being produced and moved around because of the bulk water itself and the cell's resources being diverted to cleavage rather than S phase processes.
     
  13. Kyle M

    Kyle M Member

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    P.S. - To make sure I'm being clear, I'm saying bulk water doesn't "adsorb onto proteins." Or rather, the process of bulk water adsorbing onto proteins it the process of bulk water turning into structured water. So the presence of unusually large amounts of bulk water indicates a problem of protein production/coordination/folding or perhaps a destabilizing influence of an exogenous molecule like estrogen. The ratio between bulk and structured water isn't a static thing but a continuous process, so the increase in bulk water means that the process is moving into an unstructured state.
     
  14. Travis

    Travis Member

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    Well I do know that 2-methoxyestradiol is the most potent endogenous microtubule depolymerizer found to date, a structure which needs to be dissolved before mitosis can occur. I am fairly certain that there also needs to be a significant reorganization of the centriole and cytoskeletal components upon each cell division. Thinking along these lines might perhaps place the enzyme COMT in the driver's seat for microtubular disassembly/reassembly, along with GTP and thyroid hormone (both shown to catalyze the rate of microtubule polymerization/growth).

    D'Amato, R. "2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site." Proceedings of the National Academy of Sciences (1994)

    Reiser, F. "Inhibition of normal and experimental angiotumor endothelial cell proliferation and cell cycle progression by 2-methoxyestradiol." Proceedings of the Society for Experimental Biology and Medicine (1998)

    Dawling, S. "Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens: comparison of wild-type and variant COMT isoforms." Cancer research (2001)

    Onay, U. "Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk." BMC cancer (2008)
    So perhaps estradiol could have a nongenomic effect: inhibiting microtubule polymerization and/or catalyzing their dissolution. Calcium also prevents mictrotubule polymerization, so much so that EDTA is nearly always used as a precaution when growing them in vitro.
     
  15. Mito

    Mito Member

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  16. Travis

    Travis Member

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    Above it had been shown that during a microarray analysis messenger RNA encoding for asparagine synthase had been induced 12.1-fold by estradiol. As this represents the largest change upon addition of this steroid, out of over 20,000 transcripts looked for, you might be tempted to imagine it as being a primary executioner for estrogen's effects. A steroid molecule in nanomole concentrations can hardly be said to do much at all without a high-affinity receptor, which influences nuclear transcription factors—or actually being one in itself—towards the synthesis of enzymes which are the true physical conductors of cellular mechanism (the steroid being merely a signal). So what's unique about asparagine? the carboxylic acid amide form of aspartate.. .

    While reading about leucine I'd stumbled across one unique effect of asparagine: It can strongly inhibit proteolysis, preventing intracellular protein breakdown which would naturally tend towards growth. Besides leucine, asparagine is the most powerful amino acid at doing this. But unlike leucine, asparagine has zero effect autolysosomes; since it works in an additive, noncompetitive fashion it must inhibit proteolysis at the proteosomes: subcellular organelles which break down smaller proteins. The assays used below could not differentiate between the two types or proteolysis—as they had measured the release of incorporated ¹⁴C-amino acids—but proteosomes are the only other significant proteolytic organelle besides (auto)lysosomes to be inhibited.

    'the combined effect of leucine and asparagine would correspond to approx. an 85% inhibition of this pathway.' ―Bjørn Grinde

    'An electron microscopic, morphometric analysis of isolated rat hepatocytes revealed a 70% decrease in the early forms of autophagic vacuoles after administration of leucine. The lysosomal degradation of protein was reduced by only about 30% under the same conditions. These observations suggest that leucine is a major regulator of the bulk autophagy observable in the electron microscope, but that this type of autophagy contributes only about one-half of the total amount of protein degraded in lysosomes. Asparagine inhibited lysosomal protein degradation more strongly than did leucine, but had no significant effect on the amount of autophagic vacuoles. Leucine and aspamgine would therefore seem to exert their effects on lysosomal protein degradation through different mechanisms.' ―Bjørn

    'These results indicate that autophagy of the type seen in the electron microscope, i.e. bulk segregation of cytoplasmic regions, is regulated only by leucine; asparagine apparently having a different mechanism of action.' ―Bjørn Grinde
    In 1988 Dutch biochemists had 'further defined conditions which lead to this inhibition.' It had been determined that alanine's inhibition of proteolysis and subsequent catalysis of growth could be inhibited with a transaminase inhibitor; this showed that it was the NH₄⁺ group that was responsible, being donated to asparatate (asparatate + NH₄⁺ ⟶ asparagine + H₂O). They had also noted the concentration of aspartate had been a significant factor in the autophagy rate. The chart below lends support to this pathway as it shows that a transaminase inhibitor—aminooxyacetate—increased autophagic inhibition in the presence of asparagine by preventing its degradation:

    'Inhibition by alanine, however, is prevented by the transaminase inhibitor aminooxyacetate, indicating that a catabolite of alanine (which could be glutamate or aspartate) is required for this effect.' ―Heleen Caro

    'In the presence of leucine, inhibition of proteolysis by low concentrations of alanine is not due to alanine itself but to a product of the catabolism of alanine.'

    asparagine.png

    'We therefore suspected that inhibition of proteolysis was related to the magnitude of the intracellular glutamate and/or aspartate concentration.' ―Heleen

    ‘inhibition of proteolysis by leucine must be due to a direct effect of this amino acid.’ ―Heleen Caro

    The presence of the enzyme asparagine synthase—upregulated 12.1-fold by estradiol—would necessarily increase the rate of asparagine formation, leading to an inhibition of protein breakdown and a net protein gain. This would especially be true in the presence of leucine since autolysosomes would be similarly inhibited, preventing those organelles from 'taking up the slack.' High estrogen in the presence of an unusually-high leucine food such as corn would appear to be a veritable recipe for cancer—leucine and asparagine together being capable of near-complete autophagy inhibition through two non-overlapping pathways. This could be why Mexico has the worlds highest incidence of cancer in the body's most estrogenic organ:

    'Some of the highest incidence rates of cervical–uterine cancer in the world are found in Latin America and the Caribbean, where over 25,000 women die annually from this type of tumor...' ―Eduardo César

    The leucine ratio of corn is so unusually-high that you might be tempted to think that it had decreased autophagy of the entire subcontinent, perhaps forming the giant Yucatán Peninsula through the mTOR pathway (lol).. .

    Caro, L. Heleen. "A combination of intracellular leucine with either glutamate or aspartate inhibits autophagic proteolysis in isolated rat hepatocytes." The FEBS Journal (1989)
    Grinde, Bjørn. "Leucine inhibition of autophagic vacuole formation in isolated rat hepatocytes." Experimental cell research (1981)
    César, Eduardo. "Barriers to early detection of cervical-uterine cancer in Mexico." Journal of Women's Health (1999)
     
  17. Travis

    Travis Member

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    'As a model for the former, asparaginase (L-asparagine amidohydrolase) is an FDA-approved enzyme that hydrolyzes asparagine to aspartic acid and is a successful therapy for acute lymphocytic leukemia.' ―Joon-Ho Sheen

    In this cancer cell line: the restriction of leucine (L), methionine (M), and glutamine (Q) were the most effective in causing apoptosis:

    leucine.png

    Sheen, Joon-Ho. "Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo." Cancer cell (2011)
     
  18. Obi-wan

    Obi-wan Member

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    No more meats. I still like a little beef for the stearic acid.
     
  19. TreasureVibe

    TreasureVibe Member

    Joined:
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    Check out my latest post in this topic, which contains an excerpt from a book which resonates with this post that cancer is estrogen driven:

    Alleged Cure For Cancer, Cancer Is A False Placenta Theory

    It basically comes down to.. That cancer is a placenta and baby growing in the wrong place. Wether this is the case in all cancers or just some, and that others have other components to it is something that ofcourse is not disclosed fully.
     
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