AMPK is a fuel sensing enzyme that is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g., glucose deprivation). In addition, metformin and thiozolidinediones, agents used to diminish insulin resistance in type 2 diabetes, have been shown to activate AMPK. Activation of AMPK increases processes that generate ATP (e.g., fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume ATP, but not acutely necessary for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity diminishes and these synthetic processes are enhanced. Investigations by others have demonstrated that prostate cancer cells require high rates of fatty acid and protein synthesis for their invasive growth and survival. In preliminary studies, we have observed an apparently selective inhibition of the growth of prostate cancer cells by three distinct AMPK activators, AICAR, rosiglitazone, and metformin. We have also found that these effects are associated with inhibition of fatty acid synthase (FAS), acetyl CoA carboxylase (ACC) and mTOR. Based on these findings, we will test the hypothesis that AMPK activation restricts the growth of prostate cancer cells by altering an array of cellular events. We will carry out studies with the following aims: (1) To confirm and extend our preliminary finding that AMPK activity is suppressed in prostate cancer cells and to explore to what extent this accounts for their increased growth/survival and altered cellular metabolism; (2) To determine whether agents that inhibit prostate cancer cell growth in vitro prevents the growth of prostate cancer xenografts and/or cause their regression; (3) To assess whether the uptake and oxidation of exogeneous fatty acids are imparied in prostate cancer cells, and if so to determine the mechanism(s) responsible for these abnormalities, and whether they are reversed by AMPK activation or inhibition of ACC and; (4) To explore the molecular mechanisms by which androgen and AMPK oppositely regulate the mTOR signaling pathway. Since AMPK can be activated by several anti-diabetic drugs and by certain adipocyte-derived hormones (e.g. adiponectin and leptin), success in this effort would suggest a novel, yet practical approach for treating prostate cancers in humans. ? ? ?
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