Angiotensin II, K and chemotherapeutic drugs increase cell resistance via ACSL4 and ABCG2 in adrenocortical carcinoma

RÍOS MEDRANO, M.A.; CASTILLO, A.F.; MALOBERTI, P.M.; ORLANDO, U.; PRADA, J.G.; PODESTÁ, E.J.

Salta

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

Sociedad Argentina de Investigaciones Bioquímica y de Biología Molecular (SAIB)

Acyl CoA synthetase 4 (ACSL4) is an enzyme that regulates steroidogenesis in physiological conditions. However, in pathological scenarios, an increase in ACSL4 expression is associated with the promotion of a highly aggressive cell phenotype in breast, prostate, colon, and liver cancer. ATP-binding cassette (ABC) transporters are transmembrane proteins that use energy through ATP hydrolysis to translocate low-weight molecules. Whereas in physiological conditions these transporters are in charge of maintaining homeostasis in different tissues, for example through steroid efflux, their participation in pathological events is associated with drug resistance, for example through chemotherapeutic drug efflux. Our group has previously reported the involvement of ACSL4 in steroidogenesis and breast cancer chemotherapy resistance, partly mediated by the regulation of the ABCG2 transporter. In this context and given that adrenocortical cells generate both steroids and highly aggressive tumors such as adrenocortical carcinoma, we used NCI-H295R, a cell line developed from a human adrenocortical tumor, as a steroidogenic and carcinogenic model to study the participation of ACSL4 and ABCG2 in chemotherapeutic drug resistance. Short-term treatment with angiotensin II or K increased ACSL4 expression and ABCG2 mRNA expression and protein levels. This treatment increased fluorescent compound efflux from cells. Inhibition assays further proved that compound efflux was mediated by ABCG2. Moreover, the continuous chemotherapeutic treatment also rendered an increase in ACSL4 and ABCG2 expression and drug efflux from cells. In addition, both pre-treatment with angiotensin II or K followed by high-concentration chemotherapeutic treatment and continuously increasing chemotherapeutic treatment induced an increase in cell survival rates as compared to non-stimulated non-treated cells. Altogether, these results suggest the participation of ACSL4 and ABCG2 in the mechanisms underlying adrenocortical carcinoma cell resistance to chemotherapy and hint at ACSL4 as a potential therapeutic target in this type of tumor to inhibit steroid synthesis, resistance to treatment and tumor growth.