ROLE OF ACYL-COA SYNTHETASE 4 IN PROSTATE CANCER CELLS

PRADA JESICA; ORLANDO ULISES; SOLANO ANGELA; PODESTA ERNESTO JORGE; MALOBERTI, PAULA M.; CASTILLO, ANA FERNANDA

Congreso; LV Annual SAIB Meeting and XIV PABMB Congress; 2019

Acyl-CoA synthetase 4 (ACSL4) is an enzyme taking part in arachidonic acid metabolism. The expression of ACSL4 has been shown to beassociated with aggressiveness of several types of cancer such as colon and hepatocellular carcinoma. ACSL4 is part of the mechanismresponsible of the aggressiveness in breast and prostate cancer cells, being increased in malignant cells, particularly in castration-resistantprostate cancer (CRPC). It plays a key role in the regulation of cell growth by controlling upstream effectors of mTOR pathway in breast cancercells. In addition, ACSL4 participates in steroid synthesis through of arachidonic acid release and induction of Steroidogenic Acute Regulatoryprotein (StAR). The aim of this work was to analyze the effect of ACSL4 inhibition in prostate cancer cells on steroidogenesis and signalingpathway regulated by this enzyme. Also we characterized the effect of PRGL493 in prostate cells, the specific ACSL4 inhibitor recentlydeveloped in our lab. PC3 prostate cancer cells treatment with PRGL493 produced a significant cell proliferation inhibition and migrationmeasured by BrdU incorporation assay and wound healing assay. Moreover, combination of sub-maximal doses of PGRL493 (5 μM) and ofdocetaxel (1 nM), a chemotherapeutic drug, generated a synergistic effect on inhibiting cell proliferation. It is known that androgen receptor(AR) expression and ACSL4 levels are inversely correlated in human prostate tumors, being associated a high ACSL4 expression with loss ofsteroid hormones sensitivity. After ACSL4 inhibition with PRGL493 we could detect an increase in AR mRNA levels in PC3 cell line throughreal time PCR. Aggressive prostate tumors are able to synthesize steroids, and even in low amounts are very important in tumor biology and inits malignant behavior. ACSL4 inhibition in PC3 produced a decrease in steroid levels detected by radioimmunoassay. Also, a decrease in StARprotein expression, the key steroidogenesis protein involved in the limiting step of steroids production, was detected. Then, we evaluated the roleof ACSL4 on mTOR pathway regulation in prostate cancer cells. We analyzed the expression of different proteins such as pS6, pGSK3αβ,pRICTOR and pAKT by Western Blot, finding a decrease in their expression after treatment with PRGL493.These results all together contribute to show the effect of ACSL4 and its new developed inhibitor on steroidogenesis, mTOR pathway, migrationand proliferation in prostate cancer cells, supporting the relevance of targeting ACSL4 in prostate cancer treatments, especially in CRPC,aggressive hormone independent tumor for which there is no fully effective treatment.