Acid/bile exposure triggers TRAIL-mediated apoptosis in esophageal cancer cells by suppressing the decoy receptors and c-FLIPR

Xiemei Meng; Zhiheng Chang; Na Che; Jinbao Wu; Tong Dang; Jianyuan Chai

doi:10.1016/j.biocel.2020.105736

Acid/bile exposure triggers TRAIL-mediated apoptosis in esophageal cancer cells by suppressing the decoy receptors and c-FLIP_R

Int J Biochem Cell Biol. 2020 May:122:105736. doi: 10.1016/j.biocel.2020.105736. Epub 2020 Mar 2.

Authors

Xiemei Meng¹, Zhiheng Chang², Na Che¹, Jinbao Wu¹, Tong Dang³, Jianyuan Chai⁴

Affiliations

¹ Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, 014030, China.
² Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, 014030, China; The First Affiliated Hospital of Soochow University, 188 Ten Zi St, Suzhou, China.
³ Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, 014030, China. Electronic address: 15947623515@163.com.
⁴ Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, 014030, China; Laboratory of Gastrointestinal Injury and Cancer, VA Long Beach Healthcare System, Long Beach, CA 90822, USA; College of Medicine, University of California, Irvine, CA, 92697, USA. Electronic address: Jianyuan.chai@gmail.com.

PMID: 32135301
DOI: 10.1016/j.biocel.2020.105736

Abstract

Esophageal adenocarcinoma essentially develops from esophageal inflammation caused by chronic GERD. During GERD episodes, the lower esophageal epithelium is repeatedly exposed to stomach acid, which often contains duodenal bile salts that prompt malignant transformation. TRAIL is one of the cytokines produced in response to such insults and targets the transformed cells exclusively. In this study, we simulated GERD episodes in vitro by exposing the cancer cells to acid or acid/bile combination and found that the cancer cells lived through acid attacks by expression of the decoy receptors and c-FLIP_R but died of TRAIL-mediated apoptosis when bile salts were present. Further investigation revealed that acid/bile exposure downregulated the decoy receptors and thereby facilitated TRAIL signaling; meantime, it inhibited protein kinase C activity and thus expedited c-FLIP_R degradation, allowing apoptosis to take place.

Keywords: Apoptosis; Esophageal adenocarcinoma; TRAIL; c-FLIP; caspase-8.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / metabolism*
Adenocarcinoma / pathology*
Apoptosis / drug effects
Bile Acids and Salts / pharmacology*
CASP8 and FADD-Like Apoptosis Regulating Protein / antagonists & inhibitors*
CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
Cell Line, Tumor
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / pathology*
Gastroesophageal Reflux / chemically induced
Gastroesophageal Reflux / metabolism
Gastroesophageal Reflux / pathology
Humans
Hydrochloric Acid / pharmacology
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
TNF-Related Apoptosis-Inducing Ligand / metabolism*
Transfection
Tumor Necrosis Factor Decoy Receptors / antagonists & inhibitors*
Tumor Necrosis Factor Decoy Receptors / metabolism

Substances

Bile Acids and Salts
CASP8 and FADD-Like Apoptosis Regulating Protein
CFLAR protein, human
Receptors, TNF-Related Apoptosis-Inducing Ligand
TNF-Related Apoptosis-Inducing Ligand
TNFSF10 protein, human
Tumor Necrosis Factor Decoy Receptors
Hydrochloric Acid

Supplementary concepts

Adenocarcinoma Of Esophagus