Genome-Wide CRISPR Screening Identifies the Tumor Suppressor Candidate OVCA2 As a Determinant of Tolerance to Acetaldehyde

Sobh, Amin; Loguinov, Alex; Stornetta, Alessia; Balbo, Silvia; Tagmount, Abderrahmane; Zhang, Luoping; Vulpe, Chris D.

doi:10.1093/toxsci/kfz037

Cited by 17 publications

(9 citation statements)

References 71 publications

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“…The levels of N 2 -ethyldG were determined in enzyme hydrolysates, following sodium cyanoborohydride reduction of DNA (20 μg) by LC-MS/MS using a published protocol and are expressed relative to the 2′-deoxyguanosine concentration of the sample …”

Section: Materials and Methodsmentioning

confidence: 99%

Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung

Peterson

Oram

Flavin

et al. 2021

Chem. Res. Toxicol.

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Tobacco smoke is a complex mixture of chemicals, many of which are toxic and carcinogenic. Hazard assessments of tobacco smoke exposure have predominantly focused on either single chemical exposures or the more complex mixtures of tobacco smoke or its fractions. There are fewer studies exploring interactions between specific tobacco smoke chemicals. Aldehydes such as formaldehyde and acetaldehyde were hypothesized to enhance the carcinogenic properties of the human carcinogen, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) through a variety of mechanisms. This hypothesis was tested in the established NNKinduced A/J mouse lung tumor model. A/J mice were exposed to NNK (intraperitoneal injection, 0, 2.5, or 7.5 μmol in saline) in the presence or absence of acetaldehyde (0 or 360 ppmv) or formaldehyde (0 or 17 ppmv) for 3 h in a nose-only inhalation chamber, and lung tumors were counted 16 weeks later. Neither aldehyde by itself induced lung tumors. However, mice receiving both NNK and acetaldehyde or formaldehyde had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that aldehydes may increase the severity of NNK-induced lung adenomas. The aldehyde coexposure did not affect the levels of NNK-derived DNA adduct levels. Similar studies tested the ability of a 3 h nose-only carbon dioxide (0, 5, 10, or 15%) coexposure to influence lung adenoma formation by NNK. While carbon dioxide alone was not carcinogenic, it significantly increased the number of NNK-derived lung adenomas without affecting NNKderived DNA damage. These studies indicate that the chemicals in tobacco smoke work together to form a potent lung carcinogenic mixture.

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Section: Materials and Methodsmentioning

confidence: 99%

Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung

Peterson

Oram

Flavin

et al. 2021

Chem. Res. Toxicol.

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“…Experimentally increased acetaldehyde concentrations obtained in ALDH knockout mice exposed to ethanol elicited an increase of acetaldehyde-DNA adducts [233]. Furthermore, the disruption of DNA repair mechanisms, such as the tumor suppressor OVCA2 [234] or tumor suppressor p53 [235], dramatically influences acetaldehyde tolerance. The aldehyde reacts with amino groups in proteins (ε-amino of Lysines and α-amino of the amino acids at the N-terminus).…”

Section: Damage Of Dna and Proteins And Epigenetic Shiftsmentioning

confidence: 99%

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers.

Rodríguez

Coveñas

2021

Preprint

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The World Health Organization identifies alcohol as a cause in several neoplasias of the oro-pharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. This study re-views ethanol's nonoxidative and oxidative metabolism and one-carbon metabolism that en-compasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals that interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol's effects on stem cells responsible for building and repairing tissues are reviewed. Cancer stem cells suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underlie and discuss potential targets that show more sensitivity to ethanol's action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological interven-tion. Specifically, research should pay attention to reestablish metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.

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“…Experimentally increased acetaldehyde concentrations obtained in ALDH knockout mice exposed to ethanol elicited an increase in acetaldehyde-DNA adducts [ 233 ]. Furthermore, the disruption of DNA repair mechanisms, such as the tumor suppressor OVCA2 [ 234 ] or tumor suppressor p53 [ 235 ], dramatically influences acetaldehyde tolerance. The aldehyde reacts with amino groups in proteins (ε-amino of lysines and α-amino of the amino acids at the N-terminus).…”

Section: Damage Of Dna and Proteins And Epigenetic Shiftsmentioning

confidence: 99%

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers

Rodríguez

Coveñas

2021

Cancers

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The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol’s nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol’s effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol’s action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.

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Genome-Wide CRISPR Screening Identifies the Tumor Suppressor Candidate OVCA2 As a Determinant of Tolerance to Acetaldehyde

Cited by 17 publications

References 71 publications

Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung

Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers.

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers

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