Abstract
The recent epidemic in obesity is the chief cause of the dramatic increase in a number of associated pathologies including diabetes, hyperlipidemia, cardiovascular disease and, most recently, cancer. Moreover, it is the chief cause behind the explosion in healthcare costs and the disquieting observation that for the first time in decades, human lifespan is decreasing for North Americans. The role of diet in cancer is particularly pertinent in the United States, where more than 60% of adults have been diagnosed as either clinically overweight or obese. The generally accepted explanation for the striking increase in obesity is that, during evolution, the scarcity of food led to the development of dominant genetic traits that favor the securing and storage of calories, which are now accentuated by the increased availability, tastefulness, abundance, and relatively low cost of food. The link between obesity and cancer is not specific for any one cancer, but is applicable to a number of cancer types including breast, colon, and prostate. The specific role of diet in mediating these effects has been difficult to resolve through epidemiological studies because such data rely on estimations of food intake, food sources, and the appropriate time periods to include in the study. In addition, endpoints in epidemiological studies are limited to factors such as tumor incidence and mortality, and little can be learned about the underlying biochemical and cellular mechanisms. Such studies are best dissected at the cellular level, then integrated with mouse models to determine the impact of specific phenomenon on human cancer. Validation for such an approach has come from studies on caloric restriction, which has been noted for some time to blunt cancer progression. Initially it was thought that the effects of caloric restriction on tumor progression were a secondary response to decreased cell growth; however, it is now recognized that this process actually impinges on key intracellular signaling pathways, particularly that of the mammalian target of rapamycin complex-1 (mTORC1). In turn this pathway is opposed by a large tumor suppressor genes including phosphatase and tensin homolog (PTEN), tuberous sclerosis complex (TSC1/2), neurofibromin (NF1), LKB1, initiation factor 4E-binding protein (4E-BP1) and programmed cell death protein 4 (PDCD4). In our laboratory we have been particularly interested in the role of two key downstream effectors of mTORC1 in obesity and cancer: 4E-BP1 and 40S ribosomal protein S6 kinase 1 (S6K1). In this talk we will particularly focus on the role of these signaling components in mediating the effects of nutrient overload in obesity and cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL03-07.
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