Selenite inhibits glutamine metabolism and induces apoptosis by regulating GLS1 protein degradation via APC/C-CDH1 pathway in colorectal cancer cells.

Junzhang Zhao,Qiuyue Zhang,Rui Zhou,Fang Huang,Kaiyuan Hui,Yali Ci,Lei Shi,Caimin Xu,Yu Hu,Yang Yang

doi:10.18632/oncotarget.13600

Abstract

Glutaminolysis is important for metabolism and biosynthesis of cancer cells, and GLS is essential in the process. Selenite is widely regarded as a chemopreventive agent against cancer risk. Emerging evidence suggests that it also has chemotherapeutic potential in various cancer types, but the mechanism remains elusive. We demonstrate for the first time that supranutritional dose of selenite suppresses glutaminolysis by promoting GLS1 protein degradation and apoptosis. Mechanistically, selenite promotes association of APC/C-CDH1 with GLS1 and leads to GLS1 degradation by ubiquitination, this process is related to induction of PTEN expression. In addition, GLS1 expression is increased in human colorectal cancer tissues compared with normal mucosae. Our data provide a novel mechanistic explanation for the anti-cancer effect of selenite from a perspective of cell metabolism. Moreover, our results indicate that glutaminolysis especially GLS1 could be an attractive therapeutic target in colorectal cancer.

Highlights

Colorectal cancer is still a major cause of cancer death in the world giving that the rate decreases owing to colonoscopy and sigmoidoscopy screening [1]
GLS1, as the key enzyme in glutamine metabolism, is a promising and potential therapeutic target giving the facts that: a) glutamine is unnecessary for normal cells while essential for cancer cells in vivo and vitro [10], b) activity or expression of GLS1 was activated or increased in several tumor origins and inhibition of activity or depression of GLS1 expression resulted in decreased proliferation rate in cancer cells [12, 14, 40] and c) oncogenes and tumor suppressor genes are involved in regulation of GLS1 [13, 48, 49]
It is proven that both selenoproteins and low molecular weight selenium metabolites contributed to anti-cancer effect of selente [51, 52]

Summary

Introduction

Colorectal cancer is still a major cause of cancer death in the world giving that the rate decreases owing to colonoscopy and sigmoidoscopy screening [1]. Cancer cell metabolism re-programming involves several aspects, in which glycolytic pathway change is of critical importance. Elevated glutamine metabolism in cancer cells has been described, which can maintain a functioning citric acid cycle and compensate for metabolic changes in cancer cells [5]. Glutamine (Gln), though generally considered as a non-essential amino acid in normal cells, is of key importance in proliferating cells and versatile in cancer cells [5, 6]. Elevated expression of GLS1 was found in different tumor types and GLS1 activity inhibition could result in decreased growth rate of both tumor cells and xenografts tumors [9,10,11]. Shin et al suggested a new molecular mechanism through which glutamate inhibited cell death by modulating a pathway involving MEK1, ERK2, GCN2, EIF2A, ATF4, TRB3, cFOS, and BID [14]. Regulation of GLS1 in different condition is rarely discussed

Objectives

Methods

Results

Conclusion