Role of Sigma-1 Receptor in Calcium Modulation: Possible Involvement in Cancer.

Ilaria Pontisso,Laurent Combettes

doi:10.3390/genes12020139

Abstract

Ca2+ signaling plays a pivotal role in the control of cellular homeostasis and aberrant regulation of Ca2+ fluxes have a strong impact on cellular functioning. As a consequence of this ubiquitous role, Ca2+ signaling dysregulation is involved in the pathophysiology of multiple diseases including cancer. Indeed, multiple studies have highlighted the role of Ca2+ fluxes in all the steps of cancer progression. In particular, the transfer of Ca2+ at the ER-mitochondrial contact sites, also known as mitochondrial associated membranes (MAMs), has been shown to be crucial for cancer cell survival. One of the proteins enriched at this site is the sigma-1 receptor (S1R), a protein that has been described as a Ca2+-sensitive chaperone that exerts a protective function in cells in various ways, including the modulation of Ca2+ signaling. Interestingly, S1R is overexpressed in many types of cancer even though the exact mechanisms by which it promotes cell survival are not fully elucidated. This review summarizes the findings describing the roles of S1R in the control of Ca2+ signaling and its involvement in cancer progression.

Highlights

IntroductionIn order to be able to regulate several physiological functions, cells need to maintain a much higher Ca2+ concentration in the endoplasmic reticulum (ER) than in the cytosol
Since increasing evidence supports the crucial role of Ca2+ in the modulation of the pathogenesis of cancer [4] and because sigma-1 receptor (S1R) is enriched in many types of tumors where it often provides a cytoprotective function, it can be expected to perform its pro-tumorigenic function by the regulation of Ca2+ homeostasis inside the cancer cells
S1R is involved in a variety of pathologies and conditions in many types of cancer cells and tumoral tissues, even though this observation remains such as neurodegenerative diseases and drug addiction

Summary

Introduction

In order to be able to regulate several physiological functions, cells need to maintain a much higher Ca2+ concentration in the ER than in the cytosol They have developed a series of mechanisms that involve the action of Ca2+ buffering proteins, releasing and importing processes to maintain the high steady-state concentration inside this organelle [3,10,11]. A decrease in luminal Ca2+ concentration is sensed by the stromal interacting molecule (STIM) proteins that localize at the membrane of the ER Upon store depletion, they oligomerize and redistribute into “puncta” at the ER-PM contact sites where they associate with and activate the ORAI channels to induce Ca2+ entry (reviewed in [27])

The Mitochondria Associated Membranes

The Sigma-1 Receptor

Sigma-1 Receptor in Cancer

Conclusions