Journal article
ALDH2 modulates autophagy flux to regulate acetaldehyde-mediated toxicity thresholds
American journal of cancer research, v 6(4), pp 781-796
2016
PMID: 27186430
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
A polymorphic mutation in the acetaldehyde dehydrogenase 2 (ALDH2) gene has been epidemiologically linked to the high susceptibility to esophageal carcinogenesis for individuals with alcohol use disorders. Mice subjected to alcohol drinking show increased oxidative stress and DNA adduct formation in esophageal epithelia where Aldh2 loss augments alcohol-induced genotoxic effects; however, it remains elusive as to how esophageal epithelial cells with dysfunctional Aldh2 cope with oxidative stress related to alcohol metabolism. Here, we investigated the role of autophagy in murine esophageal epithelial cells (keratinocytes) exposed to ethanol and acetaldehyde. We find that ethanol and acetaldehyde trigger oxidative stress via mitochondrial superoxide in esophageal keratinocytes. Aldh2-deficient cells appeared to be highly susceptible to ethanol- or acetaldehyde-mediated toxicity. Alcohol dehydrogenase-mediated acetaldehyde production was implicated in ethanol-induced cell injury in Aldh2 deficient cells as ethanol-induced oxidative stress and cell death was partially inhibited by 4-methylpyrazole. Acetaldehyde activated autophagy flux in esophageal keratinocytes where Aldh2 deficiency increased dependence on autophagy to cope with ethanol-induced acetaldehyde-mediated oxidative stress. Pharmacological inhibition of autophagy flux by chloroquine stabilized p62/SQSTM1, and increased basal and acetaldehyde-mediate oxidative stress in Aldh2 deficient cells as documented in monolayer culture as well as single-cell derived three-dimensional esophageal organoids, recapitulating a physiological esophageal epithelial proliferation-differentiation gradient. Our innovative approach indicates, for the first time, that autophagy may provide cytoprotection to esophageal epithelial cells responding to oxidative stress that is induced by ethanol and its major metabolite acetaldehyde. Defining autophagymediated cytoprotection against alcohol-induced genotoxicity in the context of Aldh2 deficiency, our study provides mechanistic insights into the tumor suppressor functions of ALDH2 and autophagy in alcohol-related esophageal carcinogenesis.
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Details
- Title
- ALDH2 modulates autophagy flux to regulate acetaldehyde-mediated toxicity thresholds
- Creators
- Koji Tanaka - Gastroenterology Division, Department of Medicine, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA; University of Pennsylvania Abramson Cancer CenterPhiladelphia, PA, USAKelly A Whelan - Gastroenterology Division, Department of Medicine, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA; University of Pennsylvania Abramson Cancer CenterPhiladelphia, PA, USAPrasanna M Chandramouleeswaran - Gastroenterology Division, Department of Medicine, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA; University of Pennsylvania Abramson Cancer CenterPhiladelphia, PA, USAShingo Kagawa - Gastroenterology Division, Department of Medicine, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA; University of Pennsylvania Abramson Cancer CenterPhiladelphia, PA, USASabrina L Rustgi - Gastroenterology Division, Department of Medicine, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA; University of Pennsylvania Abramson Cancer CenterPhiladelphia, PA, USAChiaki Noguchi - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine Philadelphia, PA, USAManti Guha - Department of Animal Biology, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania Philadelphia, PA, USASatish Srinivasan - Department of Animal Biology, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania Philadelphia, PA, USAYusuke Amanuma - Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University Kyoto, JapanShinya Ohashi - Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University Kyoto, JapanManabu Muto - Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University Kyoto, JapanAndres J Klein-Szanto - Histopathology Facility and Cancer Biology Program, Fox Chase Cancer Center Philadelphia, PA, USAEishi Noguchi - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine Philadelphia, PA, USANarayan G Avadhani - Department of Animal Biology, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania Philadelphia, PA, USAHiroshi Nakagawa - Gastroenterology Division, Department of Medicine, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA; University of Pennsylvania Abramson Cancer CenterPhiladelphia, PA, USA
- Publication Details
- American journal of cancer research, v 6(4), pp 781-796
- Publisher
- United States
- Grant note
- P30 DK050306 / NIDDK NIH HHS L30 DK103160 / NIDDK NIH HHS P30 ES013508 / NIEHS NIH HHS P01 CA098101 / NCI NIH HHS P30 CA006927 / NCI NIH HHS K26 RR032714 / NCRR NIH HHS K01 DK103953 / NIDDK NIH HHS T32 DK007066 / NIDDK NIH HHS F31 CA174176 / NCI NIH HHS K26 OD011179 / NIH HHS F32 CA174146 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000375261700005
- Other Identifier
- 991014877872004721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology