Targeting fatty acid synthase with ASC-J9 suppresses proliferation and invasion of prostate cancer cells.
Fatty acid synthase (FASN) is the key enzyme for the control of fatty acid synthesis that contributes significantly to the prostate cancer (PCa) progression. It was reported that androgens were able to induce FASN expression in PCa, and addition of the anti-androgen Casodex might suppress the androgen-induced FASN expression. However, here we found androgen-deprivation-therapy (ADT) with anti-androgens Bicalutamide (Casodex) or Enzalutamide (MDV3100) had little effect to suppress FASN expression and FASN-mediated cell growth and invasion during the castration resistant stage when the androgen concentration is 1 nM DHT (dihydrotestosterone). In contrast, the newly developed androgen receptor (AR) degradation enhancer ASC-J9® suppressed FASN expression and FASN-mediated cell growth and invasion in various PCa cell lines at 1 nM DHT. Mechanism dissection found ASC-J9® could suppress significantly the FASN expression and FASN-mediated PCa progression via the AR-dependent pathway involving AR→SREBP-1→FASN signaling in AR-positive C4-2 and LNCaP cells and via the AR-independent pathway involving the modulation of PI3K/AKT→SREBP-1→FASN signaling in AR-negative PC-3 and DU145 cells. Together, these results suggest that FASN is one of the important mechanism why the current ADT eventually fails. ASC-J9® might represent a new potential therapeutic approach to suppress FASN-mediated PCa progression via both AR-dependent and AR-independent pathways during the castration resistant stage of PCa. © 2016 Wiley Periodicals, Inc.
['Wen|Simeng|S|', 'Niu|Yuanjie|Y|', 'Lee|Soo Ok|SO|', 'Yeh|Shuyuan|S|', 'Shang|Zhiqun|Z|', 'Gao|Hengheng|H|', 'Li|Yanjun|Y|', 'Chou|Fuju|F|', 'Chang|Chawnshang|C|']
D000970:Antineoplastic Agents D001549:Benzamides D045744:Cell Line, Tumor D049109:Cell Proliferation D003474:Curcumin D054890:Fatty Acid Synthase, Type I D006801:Humans D008297:Male D009361:Neoplasm Invasiveness D009570:Nitriles D010669:Phenylthiohydantoin D011467:Prostate D011471:Prostatic Neoplasms D015398:Signal Transduction
fatty acid synthase ASC-J9® androgen deprivation therapy castration resistant prostate cancer