Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma.

Heng Lu,Mary Kay Washington,Dunfa Peng,Zheng Chen,Lihong Wang-Bishop,Wael El-Rifai,Tianling Hu,Ahmed Gomaa,Timothy C Wang,Oliver Mcdonald,Alan S Livingstone,Farah Ballout

doi:10.3390/cancers14061401

Abstract

Simple SummaryEsophageal cancer is the 6th most common cause of cancer-related deaths in 2018 worldwide, with a 5-year survival rate of around 20%. This study reported that esophageal adenocarcinoma cancer cells take advantage of unfolded protein response to survival. Our data using both in vitro cancer cell models and in vivo mice models discovered, for the first time, that Aurora kinase A hijacks pro-survival unfolded protein response in esophageal adenocarcinoma, promoting the survival of cancer cells under reflux-mediated stress conditions.Unfolded protein response (UPR) protects malignant cells from endoplasmic reticulum stress-induced apoptosis. We report that Aurora kinase A (AURKA) promotes cancer cell survival by activating UPR in esophageal adenocarcinoma (EAC). A strong positive correlation between AURKA and binding immunoglobulin protein (BIP) mRNA expression levels was found in EACs. The in vitro assays indicated that AURKA promoted IRE1α protein phosphorylation, activating prosurvival UPR in FLO-1 and OE33 cells. The use of acidic bile salts to mimic reflux conditions in patients induced high AURKA and IRE1α levels. This induction was abrogated by AURKA knockdown in EAC cells. AURKA and p-IRE1α protein colocalization was observed in neoplastic gastroesophageal lesions of the L2-IL1b mouse model of Barrett’s esophageal neoplasia. The combined treatment using AURKA inhibitor and tunicamycin synergistically induced cancer cell death. The use of alisertib for AURKA inhibition in the EAC xenograft model led to a decrease in IRE1α phosphorylation with a significant reduction in tumor growth. These results indicate that AURKA activates UPR, promoting cancer cell survival during ER stress in EAC. Targeting AURKA can significantly reverse prosurvival UPR signaling mechanisms and decrease cancer cell survival, providing a promising approach for the treatment of EAC patients.

Highlights

There are two main types of esophageal cancer: squamous cell carcinoma, which occurs in the upper part of the esophagus, and adenocarcinoma, which develops at the junction of the esophagus and stomach [2]
To further test the correlation between Aurora kinase A (AURKA) and Unfolded protein response (UPR) in esophageal adenocarcinoma (EAC), next-generation sequencing (NGS) analysis was performed between AURKA inhibitor treatment groups and control groups in FLO-1, OE33, and SK-GT4 cells
Since few reports are published on the relationship of AURKA and endoplasmic reticulum (ER) stress, we further looked at our esophageal tissue samples and the TCGA database for binding immunoglobulin protein (BIP) mRNA, a marker of ER stress

Summary

Introduction

Esophageal cancer is the 7th most commonly occurring cancer in men and the 13th most commonly occurring cancer in women globally [1]. It is the 6th most common cause creativecommons.org/licenses/by/ 4.0/). There are two main types of esophageal cancer: squamous cell carcinoma, which occurs in the upper part of the esophagus, and adenocarcinoma, which develops at the junction of the esophagus and stomach [2]. Most esophageal cancers in the United States are adenocarcinomas, while squamous cell carcinoma is globally common [3]. The 5-year survival rate is about 20% for all patients with all esophageal cancer stages, making esophageal cancer one with the lowest. 5-year relative survival rate from 2010 to 2016 [4]. As compared with the overall 5-year survival rate for esophageal cancer, the 5-year survival rate of esophageal adenocarcinoma is approximately 17–19% [5]

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