Inhibition of Fatty Acid Synthase in Prostate Cancer by Olristat, a Novel Therapeutic
Annual rept. 1 Nov 2005-31 Oct 2006
WAKE FOREST UNIV WINSTON-SALEM NC SCHOOL OF HEALTH SCIENCES
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The overall goal of this project 5 to understand the anti-tumor effects of FAS inhibitors. We have followed up on our previous findings by further evaluating the role of ER stress in tumor cells treated with FAS inhibitors. Our results suggest that ER stress may initiate the cell death program when FAS is inhibited in prostate tumor cell lines. Moreover, the data also suggest that the ER may sense fatty acid levels in tumor cells. A further connection to ER stress was discovered by showing that other ER stressing agents like Velcade induce fatty acid synthase activity and sensitize cells to the effects of FAS inhibitors. We have also made the novel observation that FAS expression is regulated by the src oncogene and that FAS inhibitors can block src driven matrigel invasion. Combined these data provide insight into how disruption of the FAS axis can be further exploited to inhibit prostate tumor growth and metastases. We have also extended our previous crystallography studies by solving the crystal structure of FAS bound to a cleaved orlistat. These data will provide valuable insight into future drug discovery and design within the FAS pathway. In total, we have made great strides toward understanding the anti-tumor effects of orlistat and other FAS inhibitors in prostate cancer through a multi-disciplinary approach combining cell biology, biochemistry and crystallography.
- Anatomy and Physiology
- Medicine and Medical Research