ArticleCarcinogenesis2024
ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment.
Article in Carcinogenesis, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Who cites it
9 citing papers in PubMed, 12 citations in OpenAlex.
- Common human ALDH1B1 and ALDH2 variants increase neuroinflammatory response to a single ethanol dose in mice.Science advances · 2026Article
- Short- and Long-Term Outcomes after Pancreatectomy for Pancreatic Cancer in Patients with Prior Esophagectomy for Esophageal Cancer.Annals of surgical oncology · 2026Article
- Alcohol addiction and Alzheimer's disease: a molecular collision course.Translational psychiatry · 2025Review
- ALDH2 in autophagy and cell death: molecular mechanisms and implications for diseases.Military Medical Research · 2025Review
- Lessons learned from aldehyde dehydrogenases as non-P450 aldehyde-oxidizing enzymes: implications for the 'exposome' and human health.Expert opinion on drug metabolism & toxicology · 2025Review
- Alda‑1 restores ALDH2‑mediated alcohol metabolism to inhibit the NF‑κB/VEGFC axis in head and neck cancer.International journal of molecular medicine · 2025Article
- Alcohol in Daily Products: Health Risks, Cultural Considerations, and Economic Impacts.Risk management and healthcare policy · 2025Review
- Long-term outcomes of smoker and drinker with oesophageal squamous cell carcinoma after oesophagectomy: a large-scale propensity score matching analysis.BMJ open gastroenterology · 2024Article
- Uncovering newly identified aldehyde dehydrogenase 2 genetic variants that lead to acetaldehyde accumulation after an alcohol challenge.Journal of translational medicine · 2024Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.