ROLE OF ACYL-COA SYNTHETASE 4 IN PROSTATE CANCER CELLS

PRADA JG; ORLANDO UD; SOLANO AR; PODESTA EJ; MALOBERTI PM; CASTILLO AF

Ciudad de Salta

Congreso; Reunión anual conjunta de las sociedades SAIB- PABMB 2019; 2019

SAIB- PABMB

Acyl-CoA synthetase 4 (ACSL4) is an enzyme taking part in arachidonic acid metabolism. The expression of ACSL4 has been shown to beassociated with the aggressiveness of several types of cancer such as colon and hepatocellular carcinoma. ACSL4 is part of the mechanismresponsible for the aggressiveness in breast and prostate cancer cells and is increased in malignant cells, particularly in castration-resistant prostatecancer (CRPC). It plays a key role in the regulation of cell growth by controlling upstream effectors of the mTOR pathway in breast cancer cells.In addition, ACSL4 participates in steroid synthesis through arachidonic acid release and induction of Steroidogenic Acute Regulatory protein(StAR). The aim of this work was to analyze the effect of ACSL4 inhibition in prostate cancer cells on steroidogenesis and signaling pathwaysregulated by this enzyme. Also, we characterized the effect of PRGL493 in prostate cells, the specific ACSL4 inhibitor recently developed in ourlab. PC3 prostate cancer cells treated with PRGL493 produced a significant cell proliferation inhibition and migration measured by BrdUincorporation assay and wound healing assay. Moreover, the combination of sub-maximal doses of PGRL493 (5 μM) and docetaxel (1 nM), achemotherapeutic drug, generated a synergistic effect on inhibiting cell proliferation. It is known that androgen receptor (AR) expression andACSL4 levels are inversely correlated in human prostate tumors, being associated with a high ACSL4 expression with loss of steroid hormonessensitivity. After ACSL4 inhibition with PRGL493, we could detect an increase in AR mRNA levels in the PC3 cell line through real-time PCR.Aggressive prostate tumors are able to synthesize steroids, and even in low amounts are very important in tumor biology and its malignant behavior.ACSL4 inhibition in PC3 produced a decrease in steroid levels detected by radioimmunoassay. Also, a decrease in StAR protein expression, thekey steroidogenesis protein involved in the limiting step of steroid production, was detected. Then, we evaluated the role of ACSL4 on mTORpathway regulation in prostate cancer cells. We analyzed the expression of different proteins such as pS6, pGSK3αβ, pRICTOR and pAKT byWestern Blot, finding a decrease in their expression after treatment with PRGL493. These results all together contribute to show the effect ofACSL4 and its new developed inhibitor on steroidogenesis, mTOR pathway, migration and proliferation in prostate cancer cells, supporting therelevance of targeting ACSL4 in prostate cancer treatments, especially in CRPC, aggressive hormone-independent tumor for which there is nofully effective treatment.