Characterization of Acyl-CoA synthetase 4 in ovarian cancer

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

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigaciones Clínicas.; 2022

Acyl-CoA synthetase 4 (ACSL4) is involved in arachidonic acid metabolism and steroidogenesis. In pathological scenarios, increasedACSL4 level is associated with promotion of highly aggressive phenotype in breast and prostate cancer. We developed and characterized the effect of PRGL493, a specific ACSL4 inhibitor, in triplenegative breast cancer and castration-resistant prostate cancer celllines, demonstrating that decreased aggressive phenotype basedon inhibition of steroidogenesis, chemotherapeutic resistance andtumor growth. Ovarian cancer is the third most common gynecologic malignancy but first in mortality rate and there is evidencethat sex-steroid hormones have a role in ovarian carcinogenesis.Therefore, the aim was to analyze the role of ACSL4 in epithelialovarian cancer (EOC). Bioinformatic analysis based on the crossover between genetic signatures described in ovarian tumors frompatients with EOC and genes regulated by ACSL4 related to processes of proliferation, invasion, migration and transduction signalswas performed. The study showed a positive correlation for 32 of48 genes (p<0.05), with a correlation coefficient of 0.8, and 0.46(p<0.05) when analyzing genes associated with drug resistance.Immunohistochemistry of human tissue samples showed significantincrease of ACSL4 in EOC samples compared with normal tissue(p< 0.05). Western blot analysis showed an increase in ACSL4levels in A2780, OV-90 and SKOV-3 EOC lines compared with thenon-tumoral HOSE cells. A2780, OV-90 and SKOV-3 cells weretreated with PRGL493 and MTT or BrdU assays were performed. Asignificant decrease in cell proliferation was observed in EOC cellsincubated with the inhibitor vs control. The IC50 value of PRGL493was about 40 uM for EOC cell lines, showing similar results obtainedfor breast and prostate cancer cell lines. This work led to the characterization of ACSL4 in EOC and may allow future studies combiningACSL4 inhibition with clinically used chemotherapeutics.