peatypie
Member
I recently emailed RP with the following question:
His Response:
"The gene activation is often a matter of degrees, that can be offset by reducing inflammation.
Cancer Res. 2007 Oct 1; 67(19): 9286–9293.
Nitric Oxide Inactivates the Retinoblastoma Pathway in Chronic Inflammation
Lei Ying,1 Anne B. Hofseth,1 Darren D. Browning,3 Mitzi Nagarkatti,2 Prakash S. Nagarkatti,2 and Lorne J. Hofseth1
Abstract
Patients with chronic inflammatory bowel disease have a high risk of colon cancer. The molecules that initiate and promote colon cancer and the cancer pathways altered remain undefined. Here, using in vitro models and a mouse model of colitis, we show that nitric oxide (NO) species induce retinoblastoma protein (pRb) hyperphosphorylation and inactivation, resulting in increased proliferation through the pRb-E2F1 pathway. NO-driven pRb hyperphosphorylation occurs through soluble guanylyl cyclase/guanosine 3′,5′-cyclic monophosphate signaling and is dependent on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase MEK/ERK and phosphatidylinositol 3-kinase/AKT pathways. Our results reveal a link between NO and pRb inactivation and provide insight into molecules that can be targeted in the prevention of the inflammation-to-cancer sequence.
Introduction
A basic understanding of the mechanisms involved in the inflammation-to-cancer sequence is beginning to emerge. Key players include but are not limited to nuclear factor-κB (NF-κB), p53, cytokines, nitric oxide (NO) synthases, cyclooxygenases, and pattern recognition receptors (1–3). Although the onset of carcinogenesis associated with inflammation is at least in part mediated by free radical species through protein modification and DNA damage, the identification of specific free radicals and their targets remains vague. NO species are candidates due to their elevation in chronic inflammation and cancer and their ability to damage DNA and posttranslationally modify key cancer proteins (2, 4). TP53, for example, is a tumor suppressor protein that is hyperphosphorylated and activated by NO in colitis (3). It is also mutated in this disease (5). Depending on levels, NO can also activate and inhibit NF-κB activity (6, 7).
Retinoblastoma protein (pRb) is also a well-known tumor suppressor. We have recently shown that the pRb protein is hyperphosphorylated and inactivated in mice and humans with colitis. Because pRb hyperphosphorylation correlated with inducible NO synthase (iNOS) levels in our study (8), we hypothesized that NO drives pRb hyperphosphorylation as a mechanism toward pRb inactivation in colitis. Our elucidation of the underlying signaling pathways provides a more complete understanding of molecular basis of chronic inflammation-related carcinogenesis. Strategies targeting these newly recognized pathway interactions may prove beneficial to the chemoprevention or treatment of chronic inflammation and associated carcinogenesis."
This is all very complex and the science seems to be a little vague. What would be good nitric oxide antagonists and the inflamation-to-cancer sequence? A recent blood liquid biopsy identified low RB1 gene expression which seems to suggest higher probability of cancer progression.
His Response:
"The gene activation is often a matter of degrees, that can be offset by reducing inflammation.
Cancer Res. 2007 Oct 1; 67(19): 9286–9293.
Nitric Oxide Inactivates the Retinoblastoma Pathway in Chronic Inflammation
Lei Ying,1 Anne B. Hofseth,1 Darren D. Browning,3 Mitzi Nagarkatti,2 Prakash S. Nagarkatti,2 and Lorne J. Hofseth1
Abstract
Patients with chronic inflammatory bowel disease have a high risk of colon cancer. The molecules that initiate and promote colon cancer and the cancer pathways altered remain undefined. Here, using in vitro models and a mouse model of colitis, we show that nitric oxide (NO) species induce retinoblastoma protein (pRb) hyperphosphorylation and inactivation, resulting in increased proliferation through the pRb-E2F1 pathway. NO-driven pRb hyperphosphorylation occurs through soluble guanylyl cyclase/guanosine 3′,5′-cyclic monophosphate signaling and is dependent on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase MEK/ERK and phosphatidylinositol 3-kinase/AKT pathways. Our results reveal a link between NO and pRb inactivation and provide insight into molecules that can be targeted in the prevention of the inflammation-to-cancer sequence.
Introduction
A basic understanding of the mechanisms involved in the inflammation-to-cancer sequence is beginning to emerge. Key players include but are not limited to nuclear factor-κB (NF-κB), p53, cytokines, nitric oxide (NO) synthases, cyclooxygenases, and pattern recognition receptors (1–3). Although the onset of carcinogenesis associated with inflammation is at least in part mediated by free radical species through protein modification and DNA damage, the identification of specific free radicals and their targets remains vague. NO species are candidates due to their elevation in chronic inflammation and cancer and their ability to damage DNA and posttranslationally modify key cancer proteins (2, 4). TP53, for example, is a tumor suppressor protein that is hyperphosphorylated and activated by NO in colitis (3). It is also mutated in this disease (5). Depending on levels, NO can also activate and inhibit NF-κB activity (6, 7).
Retinoblastoma protein (pRb) is also a well-known tumor suppressor. We have recently shown that the pRb protein is hyperphosphorylated and inactivated in mice and humans with colitis. Because pRb hyperphosphorylation correlated with inducible NO synthase (iNOS) levels in our study (8), we hypothesized that NO drives pRb hyperphosphorylation as a mechanism toward pRb inactivation in colitis. Our elucidation of the underlying signaling pathways provides a more complete understanding of molecular basis of chronic inflammation-related carcinogenesis. Strategies targeting these newly recognized pathway interactions may prove beneficial to the chemoprevention or treatment of chronic inflammation and associated carcinogenesis."
This is all very complex and the science seems to be a little vague. What would be good nitric oxide antagonists and the inflamation-to-cancer sequence? A recent blood liquid biopsy identified low RB1 gene expression which seems to suggest higher probability of cancer progression.
