ROLE OF ACYL-COA SYNTHETASE 4 IN EPITHELIAL OVARIAN CANCER

PRADA, JESICA G.; HERNÁNDEZ, ANDREA; GARRIDO, MARITZA P.; BIGI, MARÍA M.; ORLANDO, ULISES D.; ROMERO OSSES, CARMEN ; PODESTA, ERNESTO J.; CASTILLO, ANA F.; MALOBERTI, PAULA M.

Mendoza

Congreso; LVIII Encuentro anual de la Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular; 2022

Acyl-CoA synthetase 4 (ACSL4) is an enzyme taking part in the fatty acid metabolism. ACSL4 plays a key role in arachidonic acid 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 associated to the promotion of a highly aggressive tumoral phenotype. We developed a specific ACSL4 inhibitor, PRGL493, and characterized its inhibitory effect in TNBC and CRPC in steroidogenesis, chemotherapeutic resistance and tumor growth. Since epithelial ovarian cancer (EOC) is often diagnosed in advanced stages, the available treatments are limited and the prognosis is poor. EOC is the third cause 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 new effective therapeutic strategies, the aim of this work is to study the role of ACSL4 in EOC. In previous works we have studied the gene expression signature of ACSL4 by RNA-seq, finding that ACSL4 regulates genes associated with an aggressive phenotype such as invasion, migration, proliferation, drug resistance and signal transduction. Therefore, we performed a bioinformatics analysis comparing ACSL4 signature with EOC genetic signature of patient samples obtained from public databases. Cross analysis showed a positive correlation coefficient higher than 0.5 for 38 of 42 the genes, with the correlation coefficient being 0.46 for drug resistance-associated protein genes. Immunohistochemistry was performed on biopsies obtained from patients with EOC. The analysis 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 effect of PRGL493 was tested on EOC cell lines by performing MTT and BrdU proliferation assays. Incubation in the presence of PRGL493 produced a significant decrease in cell proliferation in A2780, OV-90 and SKOV-3 cell lines compared with the incubation with vehicle as a control. The IC50 value of PRGL493 was approximately 40 µM for EOC cell lines, being similar to the IC50 value previously obtained for breast and prostate cancer cell lines. These results allow us to conclude that ACSL4 is involved in EOC ovarian tumor biology and also allow us to conclude that ACSL4 could be a therapeutic target in EOC ovarian cancer.