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Inhibition of Fatty Acid Synthase in Prostate Cancer by Orlistat, a Novel Therapeutic

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Final rept. 1 Nov 2004-31 Oct 2007

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The basic premise of this proposal was based on two important findings. The first was the discovery that fatty acid synthase FAS is overexpressed in prostate cancer as well as in many other cancers. FAS is the enzyme that catalyzes the synthesis of fatty acid from the precursors acetyl-CoA and malonyl-CoA. The fatty acids are then utilized for subsequent phospholipid synthesis and membrane biogenesis. A body of literature has demonstrated that tumor cells are addicted to FAS derived fatty acids as inhibition of FAS activity induces cell death in tumor cells. The second was the initial discovery of the FDA-approved drug Orlistat as an inhibitor of FAS. Orlistat targets the thioesterase domain of FAS and induces cell death specifically in prostate tumor cells and inhibits the growth of prostate tumor xenografts in mice. Based on these discoveries, three specific aims were proposed. They were as follows 1 to determine the cellular consequences of FAS inhibition by Orlistat, 2 to analyze the molecular basis for FAS inhibition by Orlistat, and 3 to select and characterize novel FAS inhibitor scaffolds using peptide phage display. The overall goal of this project was to understand the anti-tumor effects of FAS inhibitors. The authors have followed up the endoplasmic reticulum ER stress response. Moreover, they have identified crosstalk between the FAS and proteasome pathway that, when perturbed, enhances ER stress signaling. In addition, preliminary data suggests that the ER stress and autophagy pathways may be acting in concert when FAS activity is reduced in tumor cells. In another line of investigation, they solved the first crystal structure of a FAS domain bound to ligand as well as the structure of the thioesterase domain of FAS bound to Orlistat, in two states. Together, these data provide a framework, or blueprint, for the design of novel FAS inhibitors and an understanding of their anti-tumor mechanisms and their future translation into the clinic.

Subject Categories:

  • Biochemistry
  • Anatomy and Physiology
  • Medicine and Medical Research
  • Crystallography

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