Abstract

The G-protein-coupled estrogen receptor (GPER) mediates rapid non-genomic effects of estrogen. Although GPER is able to induce proliferation, it is down-regulated in breast, ovarian and colorectal cancer. During cancer progression, high expression levels of GPER are favorable for patients’ survival. The GPER-specific agonist G1 leads to an inhibition of cell proliferation and an elevated level of intracellular calcium (Ca2+). The purpose of this study is to elucidate the mechanism of G1-induced cell death by focusing on the connection between G1-induced Ca2+ depletion and endoplasmic reticulum (ER) stress in the estrogen receptor positive breast cancer cell line MCF-7. We found that G1-induced ER Ca2+ efflux led to the activation of the unfolded protein response (UPR), indicated by the phosphorylation of IRE1α and PERK and the cleavage of ATF6. The pro-survival UPR signaling was activated via up-regulation of the ER chaperon protein GRP78 and translational attenuation indicated by eIF2-α phosphorylation. However, the accompanying pro-death UPR signaling is profoundly activated and responsible for ER stress-induced cell death. Mechanistically, PERK-phosphorylation-induced JNK-phosphorylation and IRE1α-phosphorylation, which further triggered CAMKII-phosphorylation, are both implicated in G1-induced cell death. Our study indicates that loss of ER Ca2+ is responsible for G1-induced cell death via the pro-death UPR signaling.

Highlights

  • Estrogens have a multitude of cellular and physiological effects, ranging from the control of reproduction to the regulation of cell differentiation and proliferation

  • Our results showed that G1 inhibited proliferation of MCF-7 cells by a remarkable arrest in G2/M already 24 h after stimulation compared to the control group (Figure 1a)

  • The present study shows that G1-induced Ca2+ efflux activates the unfolded protein response (UPR) in MCF-7 cells accompanied by the activation of inositol-requiring enzyme 1α (IRE1α), PERK and activating transcription factor 6 (ATF6)

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Summary

Introduction

Estrogens have a multitude of cellular and physiological effects, ranging from the control of reproduction to the regulation of cell differentiation and proliferation. From a clinical point of view, GPER is downregulated with breast cancer (BC) tumor progression and a high expression correlates with favorable patient survival [7,8,9,10]. In case of BC anti-estrogen therapy, high GPER levels were associated with a shorter disease-free survival under tamoxifen when compared to those receiving aromatase inhibitors [14]. These conflicting observations are in line with the idea that non-specific GPER agonists, such as estrogen and tamoxifen, induce cell proliferation by GPER stimulation, thereby replacing the tamoxifen-blocked genomic estrogen signaling and activating a cross talk of GPER with growth factor signaling [15,16]

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