17b-ESTRADIOL ABROGATES APOPTOSIS IN SKELETAL MUSCLE CELLS THROUGH ESTROGEN RECEPTOR BETA

RICADO BOLAND; ANDREA VASCONSUELO; LORENA MILANESI; ANA CAROLINA RONDA; ANA RUSSO DE BOLAND

DUBLIN

Congreso; RAPID RESPONSES TO STEROID HORMONES 5TH INTERNATIONAL MEETING; 2007

In this study we report that 17b-estradiol, through estrogen receptors with non-nuclear localization, e.g. mitochondria, endoplasmic reticulum and Golgi, can regulate apoptosis in mouse skeletal muscle C2C12 cells. 17b-estradiol, at physiological concentrations, abrogates DNA damage, PARP cleavage and cytochrome c release induced by H2O2 or etoposide. This protective action of the steroid involves fast activation of the PI3K/Akt/Bad pathway. Within the same short time interval the hormone increases phosphorylation of ERK 1/2 and p38 MAPK and induces translocation of ERK 1/2 to mitochondria. Evidence was obtained suggesting that the ERK 1/2 and PI3K/Akt/Bad pathways play a role in the antiapoptotic effects of 17b-estradiol at the mitochondria level. Blocking experiments with specific antibodies and siRNAs against the estrogen receptor a (ER a) and b (ER b) isoforms, revealed that ER b mediates to a greater extent than ERa the antiapoptotic effects of 17b-estradiol. Furthermore, it was shown that the protective role of the hormone requires the participation of heat shock protein 27 (HSP27). 17b-estradiol rapidly induced phosphorylation of HSP27 and at longer exposure times increases its expression. Immunocytochemistry and co-immunoprecipitation assays demonstrated co-localization and interaction of phosphorylated and non-phosphorylated forms of the chaperone with ER b in mitochondria. Altogether, these results suggest that the antiapoptotic signal triggered by 17b-estradiol is mediated by ER b and involves rapid activation of Akt and ERK 1/2 and the participation of HSP27.