Both diabetes and cancer are prevalent diseases whose incidence is increasing worldwide and especially in countries that are undergoing rapid industrialization (i.e. Golf Countries). Lifestyle risk factors including diet, physical activity and obesity play a pivotal role in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer is increased in diabetes. A person with diabetes has a 38% higher risk of developing colon cancer compared to other people. Male diabetes patients were found to have a 20% higher risk of developing rectal cancer. While diabetes and especially type 2 diabetes and cancer share many risk factors, the biological links between the two diseases are poorly characterized. We have evidence that in human epithelial colorectal cancerous cells, either high glucose, insulin or their combination inactivates adenine monophosphate kinase (AMPK), induces the loss of function of the tumor suppressor gene, tuberous sclerosis complex 2, encoding tuberin, activates the mTOR/S6Kinase pathway and enhances the generation of mutagnic DNA, 8-oxodG. We also show that AMPK inactivation upregulates Nox1, which in turn inactivate tuberin and mTOR. These observations were associated with increased cellular proliferation, migration and fibronectin accumulation. Treatment of the cells with metformin, a potent AMPK activator or with rapamycin, an mTORC1 inhibitor, decreases the rate of cellular proliferation and migration and reverse the biochemical changes seen in cancerous cells treated with high glucose, insulin or their combination. In rodent models of diabetes, we find that loss of function of tuberin is associated with loss of function and mutations of OGG1 gene and accumulation of significant amounts of 8-oxodG and activation of the mTOR/S6Kinase pathway. These observations are paralleled by an increase in the levels of ROS production through an NADPH dependent mechanism. These observations indicate a critical role for AMPK, tuberin and mTOR in diabetes progression. These same observations were found in animal models that develop spontaneous colorectal cancer, APC mice. Activation of AMPK or blockage of mTORC1 pathways in the APC mice decreases ROS production, reverse OGG1 mutation and 8-oxo-dG accumulation in the colon and decrease tumor development. Our Findings may suggest that activation of AMPK, blockage of mTORC1 or inhibition of the NADPH oxidases pathways represent potential targets to reduce or to inhibit the onset and the progression of colorectal cancer in diabetes.


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