Significance: It is commonly believed that diabetes mellitus may be associated with cancer. Hence, diabetic patients are at higher risk for hepatocellular carcinoma, pancreatic cancer, colorectal cancer, and breast cancer, but the mechanisms that may link these two severe diseases are not well understood. Recent Advances: A number of factors have been suggested to promote tumorigenesis in diabetic patients, including insulin resistance, hyperglycemia, dyslipidemia, inflammation, and elevated insulin-like growth factor-1 (IGF-1), which may also promote pro-oxidants, and thereby alter redox homeostasis. The consequent oxidative stress associated with lipid peroxidation appears to be a possible pathogenic link between cancer and diabetes. Critical Issues: Having summarized the above aspects of diabetes and cancer pathology, we propose that the major bioactive product of oxidative degradation of polyunsaturated fatty acids (PUFAs), the reactive aldehyde 4-hydroxynonenal (4-HNE), which is also considered a second messenger of free radicals, may be the key pathogenic factor linking diabetes and cancer. Future Directions: Because the bioactivities of 4-HNE are cell-type and concentration-dependent, are often associated with inflammation, and are involved in signaling processes that regulate antioxidant activities, proliferation, differentiation, and apoptosis, we believe that further research in this direction could reveal options for better control of diabetes and cancer. Controlling the production of 4-HNE to avoid its cytotoxicity to normal but not cancer cells while preventing its diabetogenic activities could be an important aspect of modern integrative biomedicine. Antioxid. Redox Signal. 37, 1222-1233.
Keywords: 4-hydroxynonenal; cancer; diabetes; inflammation; insulin resistance; lipid peroxidation.