It has been discovered that many human solid tumors and their precursor lesions express fatty acid synthase (FAS) and undergo high levels of fatty acid (FA) synthesis compared to most normal human tissues. FAS is the only enzyme in humans which catalyzes the de novo synthesis of fatty acids. Inhibition of FAS with a small molecule inhibitor has yielded significant anti-tumor responses in human xenografts of breast cancer, multiply drug resistant ovarian cancer, and prostate cancer, without evidence of toxicity to normal cells. FAS is suggested to be a novel target for drug development with a unique mechanism of action. Therefore, the overall goal of the studies is to investigate the mechanism of action of cancer cell death induced by FAS inhibition in vitro and in vivo. It is proposed to accomplish this goal through three specific aims. [1] To study the relationship between high levels of malonyl-CoA generated during FAS inhibition, mitochondrial dysfunction, and cancer cell apoptosis. FAS inhibition leads to mitochondrial injury in cancer cells. These studies will investigate the nature of the mitochondrial injury and its relationship to malonyl-CoA which is produced at high levels within thirty minutes of FAS inhibition. [2] To determine if malonyl-CoA acts through carnitine palmitoyltransferase-1 (CPT-1) and BCL-2 to trigger apoptosis at the outer mitochondrial membrane. CPT-1 regulates mitochondrial metabolism by regulating FA oxidation. CPT-1 in turn is regulated by malonyl-CoA. These studies test the hypothesis that malonyl-CoA acts through CPT-1 and BCL-2 to trigger cancer cell death. [3] To test the role of dietary fatty acids on FAS inhibition in vivo and to investigate the roles of malonyl-CoA and CPT-1 in vivo. FA synthesis is highly regulated in normal cells by dietary fatty acids, but cancer cells are less responsive to fatty acid regulation. Thus, modulating dietary fat could reduce FA synthesis in normal cells and increase the efficacy of FAS inhibition in vivo. Other experiments will test the mechanism of action of FAS inhibition in vivo. These studies will advance our understanding of the action of FAS inhibition, further the development of this pathway for drug development, and likely lead to additional novel therapeutic targets.
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