ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment.

Autor: Flashner S; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA., Shimonosono M; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA., Tomita Y; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA., Matsuura N; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA., Ohashi S; Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Kyoto 606-8507, Japan., Muto M; Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Kyoto 606-8507, Japan., Klein-Szanto AJ; Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA., Alan Diehl J; Case Comprehensive Cancer Center, Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA., Chen CH; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA., Mochly-Rosen D; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA., Weinberg KI; Division of Stem Cell Biology and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA., Nakagawa H; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA.; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA.
Jazyk: angličtina
Zdroj: Carcinogenesis [Carcinogenesis] 2024 Feb 12; Vol. 45 (1-2), pp. 95-106.
DOI: 10.1093/carcin/bgad085
Abstrakt: The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent among East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three-dimensional organoids and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.
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Databáze: MEDLINE
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