Fatty Acid Synthase Inhibitors Engage the Cell Death Program Through the Endoplasmic Reticulum

摘要

Fatty acid synthase (FAS), the enzyme that synthesizes the 16-carbon fatty acid palmitate, in highly expressed in prostate cancer. Because of a corresponding lack of expression in normal prostate, FAS is an attractive drug target. We have described the endoplasmic stress (ER) response as a critical mediator of the anti-tumor effects of FAS inhibitors. In this report we demonstrate the mechanism that drives the synergy between FASN inhibitors and the FDAapproved proteasome inhibitor bortezomib. Specifically we demonstrate synergy between the inhibitors and illustrate that JNK activation and CHOP expression are required to mediate ER stress-mediated death in prostate tumor cells treated with FASN inhibitors and proteasome inhibitors. We also describe the strategy to target FASN expression using a targeted knockout model in mouse prostate. This platform will be important to elucidate the role of FASN in prostate cancer. These studies will be valuable as FAS inhibitors move toward a clinical setting as a targeted therapeutic in prostate cancer.