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Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533166/ https://www.ncbi.nlm.nih.gov/pubmed/34680112 http://dx.doi.org/10.3390/biom11101479 |
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author | Shimonosono, Masataka Tanaka, Koji Flashner, Samuel Takada, Satoshi Matsuura, Norihiro Tomita, Yasuto Sachdeva, Uma M. Noguchi, Eishi Sangwan, Veena Ferri, Lorenzo Momen-Heravi, Fatemeh Yoon, Angela J. Klein-Szanto, Andres J. Diehl, J. Alan Nakagawa, Hiroshi |
author_facet | Shimonosono, Masataka Tanaka, Koji Flashner, Samuel Takada, Satoshi Matsuura, Norihiro Tomita, Yasuto Sachdeva, Uma M. Noguchi, Eishi Sangwan, Veena Ferri, Lorenzo Momen-Heravi, Fatemeh Yoon, Angela J. Klein-Szanto, Andres J. Diehl, J. Alan Nakagawa, Hiroshi |
author_sort | Shimonosono, Masataka |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8533166 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85331662021-10-23 Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy Shimonosono, Masataka Tanaka, Koji Flashner, Samuel Takada, Satoshi Matsuura, Norihiro Tomita, Yasuto Sachdeva, Uma M. Noguchi, Eishi Sangwan, Veena Ferri, Lorenzo Momen-Heravi, Fatemeh Yoon, Angela J. Klein-Szanto, Andres J. Diehl, J. Alan Nakagawa, Hiroshi Biomolecules Article 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. MDPI 2021-10-07 /pmc/articles/PMC8533166/ /pubmed/34680112 http://dx.doi.org/10.3390/biom11101479 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Shimonosono, Masataka Tanaka, Koji Flashner, Samuel Takada, Satoshi Matsuura, Norihiro Tomita, Yasuto Sachdeva, Uma M. Noguchi, Eishi Sangwan, Veena Ferri, Lorenzo Momen-Heravi, Fatemeh Yoon, Angela J. Klein-Szanto, Andres J. Diehl, J. Alan Nakagawa, Hiroshi Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy |
title | Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy |
title_full | Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy |
title_fullStr | Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy |
title_full_unstemmed | Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy |
title_short | Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy |
title_sort | alcohol metabolism enriches squamous cell carcinoma cancer stem cells that survive oxidative stress via autophagy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533166/ https://www.ncbi.nlm.nih.gov/pubmed/34680112 http://dx.doi.org/10.3390/biom11101479 |
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