ERas Enhances Resistance to Cisplatin-Induced Apoptosis by Suppressing Autophagy in Gastric Cancer Cell.

Huajian Tian,Junyang Tan,Wenjuan Jia,Xiao Meng,Qinghua Zhou,Peining Li,Miaomiao Wang,Jianshuang Li,Wenjun Wang

doi:10.3389/fcell.2019.00375

Huajian Tian, Junyang Tan + Show 7 more

Open Access

https://doi.org/10.3389/fcell.2019.00375

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Abstract

Gastric cancer (GC), a common type of malignant cancer, remains the fifth most frequently diagnosed cancer and the third leading cause of cancer-related deaths worldwide. Despite developments in the treatment of GC, the prognosis remains poor. Embryonic stem cell-expressed Ras (ERas), a novel member of the Ras protein family, has recently been identified as an oncogene involved in the tumorigenic growth of embryonic stem cells. A recent study reported that ERas is expressed in most GC cell lines and GC specimens, and it promotes tumorigenicity in GC through induction of the epithelial mesenchymal transition (EMT) and activation of the PI3K/AKT pathway. Here, we found that ERas blocked autophagy flux in BGC-823 and AGS GC cells, which may occur through activation of the AKT/mTOR signaling pathway. Moreover, ERas overexpression suppressed cisplatin-induced apoptosis, and rapamycin treatment significantly attenuated ERas-mediated cisplatin resistance in GC cells. These data suggest that ERas may be a potential therapeutic target to improve the outcomes of GC patients by regulating the autophagy process.

Highlights

Gastric cancer (GC) is one of the most common types of malignant cancer; it remains the fifth most frequently diagnosed cancer (1033701 new cases in 2018) and the third leading cause of cancerrelated deaths (8.2% in total) worldwide (Bray et al, 2018)
Embryonic stem cell-expressed Ras is a recently identified oncogene involved in the tumorigenic growth of embryonic stem cells (Takahashi et al, 2003)
expressed Ras (ERas) mRNA is expressed in several cancer cell lines, including colorectal carcinomas, pancreatic carcinomas, and breast carcinomas, but not in normal cell lines (Yasuda et al, 2007; Suarez-Cabrera et al, 2018)

Summary

INTRODUCTION

Gastric cancer (GC) is one of the most common types of malignant cancer; it remains the fifth most frequently diagnosed cancer (1033701 new cases in 2018) and the third leading cause of cancerrelated deaths (8.2% in total) worldwide (Bray et al, 2018). Autophagy is executed by ATG proteins (ULK1, BECN1, ATG3/5/7/12, and LC3 etc.) and is regulated by several signaling pathways, including PI3K/Akt/mTOR, AMPK, and P53 pathway (Cao et al, 2019). On one hand autophagy stimulation can act as a protective mechanism to prevent cancer initiation and cell growth (Liang and Jung, 2010). ERas was shown to promote the activation of the PI3K/AKT pathway and the epithelial mesenchymal transition (EMT) in GC (Aoyama et al, 2010). ERas enhances resistance to CPT-11 in GC via activation of the PI3K/mTOR pathway and NF-κB (Kubota et al, 2011). We reported here that ERas overexpression blocked autophagic flux through the AKT/mTOR signaling pathway. ERas reduced cisplatin-induced apoptosis in gastric cells and activating autophagy blocks ERas-related resistance to cisplatin. Our findings suggested that ERas might enhance resistance to apoptosis through autophagy suppression in GC cells

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