Study of the Relationship between Sigma Receptor Expression Levels and Some Common Sigma Ligand Activity in Cancer Using Human Cancer Cell Lines of the NCI-60 Cell Line Panel.

Evangelia Sereti,Elisavet Kalaitsidou,Nikos Sakellaridis,Konstantinos Dimas,Chrisiida Tsimplouli

doi:10.3390/biomedicines9010038

Evangelia Sereti, Elisavet Kalaitsidou + Show 3 more

Open Access

https://doi.org/10.3390/biomedicines9010038

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Journal: Biomedicines	Publication Date: Jan 5, 2021
Citations: 11	License type: CC BY 4.0

Affiliation: University of Thessaly, Lund University

Abstract

Sigma (σ) receptors have attracted great interest since they are implicated in various cellular functions and biological processes and diseases, including various types of cancer. The receptor family consists of two subtypes: sigma-1 (σ1) and sigma-2 (σ2). Both σ receptor subtypes have been proposed as therapeutic targets for various types of cancers, and many studies have provided evidence that their selective ligands (agonists and antagonists) exhibit antiproliferative and cytotoxic activity. Still, the precise mechanism of action of both σ receptors and their ligands remains unclear and needs to be elucidated. In this study, we aimed to simultaneously determine the expression levels of both σ receptor subtypes in several human cancer cell lines. Additionally, we investigated the in vitro antiproliferative activity of some widely used σ1 and σ2 ligands against those cell lines to study the relationship between σ receptor expression levels and σ ligand activity. Finally, we ran the NCI60 COMPARE algorithm to further elucidate the cytotoxic mechanism of action of the selected σ ligands studied herein.

Highlights

To complicate things even more, a 2018 study reported that σ2/TMEM97 forms a trimeric complex with PGRMC1 and the low-density lipoprotein receptor (LDLR), which is responsible for the rapid internalization of the low-density lipoprotein (LDL) in HeLa cells, a human cervical cancer cell line [8]
It is undisputed that σ1 receptor is an allosteric modulator of multiple cellular signaling systems that, in the context of cancer, act as a chaperone protein, which is a component of the cancer cell support machinery [27]
The function of σ2 receptor remains a mystery and to make things more complex, recent studies show that PGRMC1 and TMEM97 may cooperate and form a ternary complex of LDLR–PGRMC1–TMEM97 that results in the rapid internalization of LDL by LDLR in HeLa cells [8]

Summary

Introduction

A few years later in 2017, Alon et al published evidence showing that the sigma-2 receptor is identical to TMEM97 [6], which is the prevailing theory. Sigma-2/TMEM97, a member of the insulin-like growth factor binding proteins, is a protein that is reported to be increased in several types of cancer [7]. To complicate things even more, a 2018 study reported that σ2/TMEM97 forms a trimeric complex with PGRMC1 and the low-density lipoprotein receptor (LDLR), which is responsible for the rapid internalization of the low-density lipoprotein (LDL) in HeLa cells, a human cervical cancer cell line [8]. That work suggested that both PGRMC1 and TMEM97 could be part of a more complex receptor that can bind σ2-ligands

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