Resveratrol modulates the phosphoinositide 3‐kinase pathway through an estrogen receptor α‐dependent mechanism: Relevance in cell proliferation

Abstract

Resveratrol (RES), a natural phytoalexin, has antiproliferative activity in human‐derived cancer cells and in rodent models of tumor development. We have previously shown that RES induced apoptotic death in estrogen‐responsive MCF‐7 human breast cancer cells. Recent data have indicated that the estrogen receptor‐α (ERα), through interaction with p85, regulates phosphoinositide 3‐kinase (PI3K) activity, revealing a physiologic, nonnuclear function of the ERα potentially relevant in cell proliferation and apoptosis. In our study, using MCF‐7, we have analyzed the ability of RES to modulate the ERα‐dependent PI3K pathway. Immunoprecipitation and kinase activity assays showed that RES increased the ERα‐associated PI3K activity with a maximum stimulatory effect at concentrations close to 10 μM; concentrations >50 μM decreased PI3K activity. Stimulation of PI3K activity by RES was ERα‐dependent since it could be blocked by the antiestrogen ICI 182,780. RES did not affect p85 protein expression but induced the proteasome‐dependent degradation of the ERα. Nevertheless, the amount of PI3K immunoprecipitated by the ERα remained unchanged in presence of RES, indicating that ERα availability was not limiting PI3K activity. Phosphoprotein kinase B (pPKB/AKT) followed the pattern of PI3K activity, whereas RES did not affect total PKB/AKT expression. PKB/AKT downstream target glycogen synthase kinase 3 (GSK3) also showed a phosphorylation pattern that followed PI3K activity. We propose a mechanism through which RES could inhibit survival and proliferation of estrogen‐responsive cells by interfering with an ERα‐associated PI3K pathway, following a process that could be independent of the nuclear functions of the ERα.