CONICET | Buscador de Institutos y Recursos Humanos

Estrogens exert antiapoptotic effects in various cell types, e.g. vascular endothelial, smooth muscle and breast cancer cells. We have previously reported that 17beta-estradiol inhibits apoptosis through estrogen receptors with non-nuclear localization, e.g. mitochondria and endoplasmic reticulum, in the mouse skeletal muscle C2C12 cell line. The steroid hormone abrogates DNA damage, PARP cleavage and cytochrome c release induced by H2O2 or etoposide. This mechanism involves fast activation of the PI3K/Akt/Bad pathway. It was demonstrated that the estrogen also triggers rapid phosphorylation of ERK 1/2 and p38 MAPK. Using specific inhibitors it was shown that both MAPKs mediate the effects of estradiol on Akt and Bad phosphorylation, cytochrome c and Smac/Diablo release, caspase 3 and PARP cleavage, and morphological changes of the cells. Interestingly, we found that ERK1/2 activated by 17beta-estradiol is located mainly in mitochondria. Parallel studies showed that the interaction between proapoptotic kinase ASK-1 with phospho-Akt increases in presence of estrogen. This fact suggests another possible point of negative regulation of apoptotic cascade by Akt. Furthermore, evidence was obtained that 17beta-estradiol at longer exposure times increases the expression of HSP27. Assays under apoptotic conditions linked this chaperone to the protective action of the hormone, specifically regulating caspase-3 activity. Immunocytochemistry and co-immunoprecipitation assays revealed interaction of HSP27 and ER beta in mitochondria. Altogether, these data imply that ERK 1/2, p38 MAPK, ASK-1 and HSP27 play a role in the mechanism underlying the antiapoptotic action of 17beta-estradiol in skeletal muscle cells.

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