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

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2021-10, Vol.11 (10), p.1479
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alcohol; Alcohol Drinking - metabolism; Animals; Apoptosis; Autophagy; Biopsy; Cancer therapies; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; CD44; CD44 antigen; Cell culture; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cloning; Depolarization; Esophageal carcinoma; Esophagus; Ethanol; Ethanol - metabolism; Flow cytometry; Gene expression; Head and neck; Homeostasis; Humans; Hyaluronan Receptors - metabolism; Life sciences; Membrane Potential, Mitochondrial; Metabolism; Metabolites; Metastasis; Mice; Mice, SCID; Mitochondria; Mitochondria - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Organoids; Organoids - pathology; Oxidation-Reduction; Oxidative Stress; Patients; Phagocytosis; Risk factors; Squamous cell carcinoma; Stem cells; Therapeutic targets; Transplantation; Tumors; Xenografts
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom11101479

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. 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). 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. 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.