Survival versus apoptotic 17β‐estradiol effect: Role of ERα and ERβ activated non‐genomic signaling

Abstract

The capability of 17beta-estradiol (E2) to induce the non-genomic activities of its receptors (ER alpha and ER beta) and to evoke different signaling pathways committed to the regulation of cell proliferation has been analyzed in different cell cancer lines containing transfected (HeLa) or endogenous (HepG2, DLD1) ER alpha or ER beta. In these cell lines, E2 induced different effects on cell growth/apoptosis in dependence of ER isoforms present. The E2-ER alpha complex rapidly activated multiple signal transduction pathways (i.e., ERK/MAPK, PI3K/AKT) committed to both cell cycle progression and apoptotic cascade prevention. On the other hand, the E2-ER beta complex induced the rapid and persistent phosphorylation of p38/MAPK which, in turn, was involved in caspase-3 activation and cleavage of poly(ADP-ribose)polymerase, driving cells into the apoptotic cycle. In addition, the E2-ER beta complex did not activate any of the E2-ER alpha-activated signal molecules involved in cell growth. Taken together, these results demonstrate the ability of ER beta isoform to activate specific signal transduction pathways starting from plasma membrane that may justify the effect of E2 in inducing cell proliferation or apoptosis in cancer cells. In particular this hormone promotes cell survival through ER alpha non-genomic signaling and cell death through ER beta non-genomic signaling.

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

“…The presence of both ERa and ERb and/or several isoforms of each may account for the observed biphasic response to estrogen agonists. Recent reports suggested the importance of ERb as a negative regulator of ERa function in the nucleus (Petersen et al, 1998;Pettersson et al, 2000) and in cytosol (Acconcia et al, 2005b). Truncated isoforms of ERa can also dimerize with the full size isoform (Stauffer et al, 2000).…”

ERβ in breast cancer—Onlooker, passive player, or active protector?

“…In ER-cells, introduction of ERα or ERβ permits E2 activation of G proteins and MAPK [42]. E2 stimulates MAPK and Akt and is anti-apoptotic in ERα-transfected HeLa cells, but activates p38 and apoptosis in ERβ-transfected cells [51].…”

Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities

“…The mechanism by which E2 exerts proliferative properties has been assumed to be exclusively mediated by ERα-induced rapid membrane-starting actions (Marino et al, 1998;Castoria et al, 1999;Lobenhofer et al, 2000;Marino et al, 2001;Castoria et al, 2001;Marino et al, 2002;Marino et al, 2003;Acconcia et al, 2005b), whereas E2 induces cell death through ERβ nongenomic signaling (Acconcia et al, 2005b). In the nervous system, E2 influences neural functions (e.g., cognition, behavior, stress responses, and reproduction) in part inducing such rapid responses (Farach-Carson and Davis, 2003;Losel et al, 2003).…”