Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy.

Masataka Shimonosono,Fatemeh Momen-Heravi,Andres J Klein-Szanto,Veena Sangwan,Samuel Flashner,Norihiro Matsuura,Satoshi Takada,Yasuto Tomita,Lorenzo Ferri,Angela J Yoon,J Alan Diehl,Hiroshi Nakagawa,Koji Tanaka,Eishi Noguchi,Uma M Sachdeva

doi:10.3390/biom11101479

Abstract

Background: Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood. Methods: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how EtOH exposure influences intratumoral SCC cell populations including putative cancer stem cells defined by high CD44 expression (CD44H cells). Results: Using 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we found that EtOH is metabolized via alcohol dehydrogenases to induce oxidative stress associated with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis of the majority of SCC cells within organoids. However, CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH. Importantly, inhibition of autophagy increased EtOH-mediated apoptosis and reduced CD44H cell enrichment, xenograft tumor growth, and organoid formation rate. Conclusions: This study provides mechanistic insights into how EtOH may influence SCC cells and establishes autophagy as a potential therapeutic target for the treatment of EtOH-associated SCC.

Highlights

Chronic alcohol consumption poses increased risks for many cancer types [1]
We found that EtOH metabolism in squamous cell carcinoma (SCC) cells leads to oxidative stress, mitochondrial dysfunction, and apoptosis of non-CD44H cells, permitting enrichment of
This study provides mechanistic insights describing how EtOH metabolism may influence both CSC and non-CSC subpopulations of HNSCC and ESCC tumors and organoids

Summary

Introduction

Chronic alcohol consumption poses increased risks for many cancer types [1]. The foremost organ sites linked to a strong alcohol-related cancer risk are the mouth, tongue, throat and the esophagus [2,3] where squamous cell carcinoma (SCC) represents the major tumor type. In normal human esophageal epithelial cell lines, cytochrome P450 2E1 and alcohol dehydrogenase (ADH) 1B catalyze EtOH oxidation, which generates acetaldehyde, a toxic metabolite that induces cell injury by perturbing mitochondrial respiration and the electron transportation chain, causing oxidative stress and apoptosis [10]. Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). Results: Using 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we found that EtOH is metabolized via alcohol dehydrogenases to induce oxidative stress associated with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis of the majority of SCC cells within organoids. CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH.

Methods

Results

Discussion

Conclusion