EGF REGULATES THE GEN EXPRESSION OF ENZYMES EVOLVED IN AA RELEASE

R. CASTILLA; M. GADALETA; F. CASTILLO; A. DUARTE; A. LAGO; C. PAZ; E.J. PODESTÁ

Mar del Plata

Congreso; XLIII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2007

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB)

The epidermal growth factor (EGF) promotes cell growth by AA release. In MA10 mouse Leydig cells EGF promotes AA release and its metabolization to lipoxygenated products. However the mechanism by which EGF releases AA in these cells was unknown. Steroidogenic hormones release AA for steroids synthesis by a concerted action of an acyl-CoA synthetase (ACS4) and an Acyl-CoA thioesterase (Acot2). These hormones increase ACS4 protein levels and regulate Acot2 by phosphorylation and substrate availability. Here we show that EGF produces a mitochondrial AA increment which is released by Acot2 action, as was demonstrated in Acot2 down or overexpression experiments. This AA, in turn, regulates StAR protein expression, an indirect evidence of its metabolization to lipoxygenated products. EGF increased ACS4 and Acot2 mRNA in MA10 and Y1 adrenal cells. The Acot2 induction was described before in liver by peroxisome proliferator action and fasting, and in diabetic rat heart. ACS4 is overexpressed in colon and hepatocellular carcinoma. This is the first time that a growth factor regulation of these enzymes was described. Since EGF is involved in cell transformation to a tumoral state through AA release and metabolization by lipoxygenases, these results suggest that EGF-stimulated AA tumorigenic effects may be induced by the AA release in a specific compartment of the cell, i.e. the mitochondria