β-Arrestin1 inhibits chemotherapy-induced intestinal stem cell apoptosis and mucositis

Y Zhan,B Wu,C Xu,S Tan,H Liu,Y Yang,J Jiang,Z Liu,J Chen

doi:10.1038/cddis.2016.136

Abstract

The mechanism of chemotherapy-induced gastrointestinal (GI) syndrome (CIGIS) is still controversial, and it is unclear whether chemotherapy induces intestinal stem cell (ISC) apoptosis. β-Arrestins are regulators and mediators of G protein-coupled receptor signaling in cell apoptosis, division and growth. In this study, we aimed to investigate whether chemotherapy induces ISC apoptosis to contribute to mucositis in CIGIS and whether β-arrestin1 (β-arr1) is involved in this apoptosis. Different chemotherapeutic agents were used to generate a CIGIS model. Lgr5-EGFP-IRES-creERT2+/− knock-in mice were used as a CIGIS model to investigate ISC apoptosis. β-arr1 knockout mice were used to determine whether β-arr1 is involved in the apoptosis in CIGIS. Intestinal histology was performed, the ISC apoptosis was analyzed and the mucosal barrier was examined. The effects of β-arr1 in apoptosis were investigated in the samples from humans and mice as well as in cell lines. Here, we demonstrate that chemotherapy induced intestinal mucositis by promoting crypt cell apoptosis, especially in Lgr5+ stem cells and Paneth cells but not in goblet cells, epithelial cells or vascular endothelial cells. Furthermore, β-arr1 deficiency exacerbated the Lgr5+ stem cell apoptosis, but not Paneth cell apoptosis, in CIGIS. In addition, the data showed that β-arr1 reduced the chemotherapy-induced Lgr5+ stem cell apoptosis by inhibiting endoplasmic reticulum stress-mediated mitochondrial apoptotic signaling. Our study indicates that β-arr1 inhibits chemotherapy-induced ISC apoptosis to alleviate intestinal mucositis in CIGIS.

Highlights

Others proposed that the decrease in goblet cells alters mucin secretion and intestinal flora, which leads to intestinal mucositis.[3]
Our study showed that intestinal crypt cells underwent apoptosis in chemotherapy patients with chemotherapyinduced GI syndrome (CIGIS) but not in non-chemotherapy patients (Figure 1)
Our study showed that chemotherapy induces small intestinal crypt cell apoptosis in humans and mice, in leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)+ stem cells

Summary

Introduction

Others proposed that the decrease in goblet cells alters mucin secretion and intestinal flora, which leads to intestinal mucositis.[3]. Recent studies demonstrated that progenitor cell apoptosis was induced by chemotherapeutic drugs.[4] A study by our group found that chemotherapy increased intestinal crypt cell apoptosis and inhibited proliferation.[5] no studies have explained the relationship between intestinal stem cells (ISCs) and CIGIS. Several signaling pathways have been shown to regulate chemotherapy-induced apoptosis in the crypt cells, including the p53 pathway, which was identified in our recent study.[5] β-arrestin[1] (β-arr1) was originally classified as a G proteincoupled receptor (GPCR) but was later shown to have much broader and more versatile roles. Β-arr[1] reduced the chemotherapy-induced Lgr5+ stem cell apoptosis by inhibiting ER stress-mediated mitochondrial apoptotic signaling to alleviate intestinal mucositis in CIGIS

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