ACYL-COA SYNTHETASE 4 INHIBITION DECREASES ADRENOCORTICAL HUMAN CELL PROLIFERATION SUSTAINED BY ANGIOTENSIN II.

HELFENBERGER, KATIA E.; FIORE, ANA; HERRERA, LUCÍA; BENZO, YANINA; MALOBERTI, PAULA; PODEROSO, CECILIA

Buenos Aires

Congreso; Reunión conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Investigación Clínica (SAIC)

Angiotensin II (Ang II) is one of the most important stimuli of adrenalglomerulosa cells. Ang II stimulates proliferation of adrenocorticalcells in vivo and primary bovine glomerulosa cells in vitro, althoughrat glomerulosa cells in vitro exhibit hypertrophy rather than proliferationby Ang II. Then, proliferating effects of Ang II rely on multiplefactors. In adrenal cells, proliferation depends on the activation ofthe PI3K/Akt/mTOR pathway, which is overactive in adrenocorticaltumor and others. The enzyme acyl-CoA synthetase 4 (ACSL4)activates mTOR, promoting phosphorylation of its componentsand inducing proliferation in breast cancer cells. ACSL4 is highlyexpressed in adrenal gland regulated by Ang II and involved in aldosteronesynthesis, in H295R adrenocortical human cells. The aim ofthis work is to study a possible role of ACSL4 in Ang II-modulation ofmTOR pathway and proliferation in human adrenocortical cells. Weused H295R human adrenocortical cell line that responds to AngII stimulation. We observed by immunoblot that Ang II promotes atime-dependent phosphorylation of Ribosomal protein S6 (RpS6),activated downstream mTOR pathway. RpS6 phosphorylation is significantlydecreased when cells were treated with Triacsin C (T), apotent ACSL4 inhibitor (Ang II vs. Ang II + T; 4h: 4.71 vs. 0.66; 6h:5.41 vs. 1.05 ***p<0.001, relativized to control). Then, we assessedproliferation of H295R Ang II-treated cells with or without TriacsinC. H295R cells were subjected to BrdU incorporation assay usingan ELISA kit. We observed that Ang II-sustained proliferation at 72hwas diminished by Triacsin C, while basal cell proliferation was unaffected(Ang II vs. Ang II + T; 0.86 vs. 0.41 OD 450 nm **p<0.05).ACSL4 inhibition showed a decreased redox cellular activity of AngII-treated cells, measured by MTT assay. These results suggest arole for ACSL4 in Ang II-sustained proliferation, possibly mediatedby mTOR pathway activation in adrenocortical human cells.