ROLE OF ACYL-COA SYNTHETASE 4 IN EPITHELIAL OVARIAN CANCER

PRADA, JESICA G.; HERNANDEZ ANDREA; GARRIDO MARITZA; BIGI, MARÍA M.; ORLANDO, ULISES DANIEL; ROMERO OSSES, CARMEN; PODESTA, ERNESTO JORGE; MALOBERTI, PAULA M.

Congreso; LVIII Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research; 2022

Acyl-CoA synthetase 4 (ACSL4) is an enzyme taking part in the fatty acid metabolism. ACSL4 plays a key role in arachidonicacid metabolism and in steroidogenesis. We and others have described the role of ACSL4 in breast and prostate cancer. Particularly,in triple-negative breast cancer (TNBC) and in castration-resistance prostate cancer (CRPC), increased ACSL4 levels are associatedto the promotion of a highly aggressive tumoral phenotype. We developed a specific ACSL4 inhibitor, PRGL493, and characterizedits inhibitory effect in TNBC and CRPC in steroidogenesis, chemotherapeutic resistance and tumor growth. Since epithelial ovariancancer (EOC) is often diagnosed in advanced stages, the available treatments are limited and the prognosis is poor. EOC is the thirdcause of gynecologic malignancy but the first one of dead. Of the total of the ovarian primary tumors, the 90% corresponds to EOC.Sex-steroid hormones may have a relevant role in the development and progression of EOC. Given the need to develop neweffective therapeutic strategies, the aim of this work is to study the role of ACSL4 in EOC. In previous works we have studied thegene expression signature of ACSL4 by RNA-seq, finding that ACSL4 regulates genes associated with an aggressive phenotypesuch as invasion, migration, proliferation, drug resistance and signal transduction. Therefore, we performed a bioinformaticsanalysis comparing ACSL4 signature with EOC genetic signature of patient samples obtained from public databases. Cross analysisshowed a positive correlation coefficient higher than 0.5 for 38 of 42 the genes, with the correlation coefficient being 0.46 for drugresistance-associated protein genes. Immunohistochemistry was performed on biopsies obtained from patients with EOC. Theanalysis showed increased levels of ACSL4 in the EOC human tissue samples compared to normal tissue samples. Subsequently,the expression of ACSL4 was compared between EOC cell lines (A2780, OV-90 and SKOV-3) and the non-tumor cell line HOSE.Western blot analysis showed an increased levels of ACSL4 in EOC cell lines relative to HOSE cells. Then, the inhibitory effectof PRGL493 was tested on EOC cell lines by performing MTT and BrdU proliferation assays. Incubation in the presence ofPRGL493 produced a significant decrease in cell proliferation in A2780, OV-90 and SKOV-3 cell lines compared with theincubation with vehicle as a controlThe IC50 value of PRGL493 was approximately 40 µM for EOC cell lines, being similar to the IC50 value previously obtained forbreast and prostate cancer cell lines. These results allow us to conclude that ACSL4 is involved in EOC ovarian tumor biology andalso allow us to conclude that ACSL4 could be a therapeutic target in EOC ovarian cancer.