Influence of pharmacologic ALDH2 activation on alcohol-driven tumor progression in ALDH2-deficient esophageal squamous cell carcinoma models.

Abstract

e15171 Background: Esophageal squamous cell carcinoma (ESCC) is highly prevalent in East Asia and strongly linked to alcohol consumption. Aldehyde dehydrogenase 2 (ALDH2) deficiency, common in East Asian populations, leads to acetaldehyde accumulation, a WHO Group I carcinogen, and is a major genetic risk factor for ESCC. However, how ALDH2-deficient tumors biologically adapt to chronic alcohol exposure and whether pharmacologic ALDH2 activation can mitigate tumor progression remain unclear. Methods: We investigated alcohol-associated tumor phenotypes using ESCC cell lines with distinct ALDH2 status: ALDH2-deficient KYSE510 and ALDH2–wild-type KYSE270. Cells were treated with ethanol with or without ALDH2 activators (Alda-1, Alda-64). Cell viability (MTT, CCK-8), clonogenicity, apoptosis signaling, and epithelial–mesenchymal transition (EMT) markers were assessed. In vivo, subcutaneous tumors were established using MOC1 cells in mice stratified by ALDH2 genotype and alcohol exposure, followed by treatment with Alda-1 or Alda-64. Results: ALDH2 activators were non-cytotoxic and enabled evaluation under physiologic alcohol exposure ( < 2% ethanol). In ALDH2-deficient KYSE510 cells, ALDH2 activator treatment increased ALDH2 protein expression, a response not observed in ALDH2–wild-type KYSE270 cells. KYSE510 cells demonstrated enhanced alcohol tolerance, reduced apoptosis-related signaling, and phenotypic adaptation consistent with metabolic reprogramming, whereas KYSE270 cells retained alcohol responsiveness, highlighting intertumoral heterogeneity. ALDH2 activation modulated malignant phenotypes under alcohol exposure. Alda-64 was associated with decreased N-cadherin and increased E-cadherin expression, suggesting suppression of EMT-related progression. In vivo, alcohol-fed ALDH2-mutant mice showed significantly accelerated tumor growth compared with other groups, demonstrating a synergistic effect of ALDH2 deficiency and alcohol exposure. Notably, Alda-64 treatment reduced tumor volume by approximately 20–30% in ALDH2-mutant alcohol-exposed mice compared with Alda-1 and control groups, indicating a selective antitumor effect in the high-risk genetic and environmental context. Conclusions: ALDH2 deficiency drives adaptive tumor survival and progression under alcohol exposure and contributes to biologically aggressive ESCC phenotypes. Pharmacologic ALDH2 activation, particularly with Alda-64, attenuates alcohol-driven tumor progression and EMT-associated changes. These findings support ALDH2 as a metabolism-based therapeutic target and provide a precision prevention and treatment rationale for alcohol-associated ESCC.