title: Aldo-keto reductase 1B10 protects human colon cells from DNA damage induced by electrophilic carbonyl compounds.
abstract: Electrophilic carbonyl compounds are highly cytotoxic and genotoxic. Aldo-keto reductase 1B10 (AKR1B10) is an enzyme catalyzing reduction of carbonyl compounds to less toxic alcoholic forms. This study presents novel evidence that AKR1B10 protects colon cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 is specifically expressed in epithelial cells of the human colon, but this study found that AKR1B10 expression was lost or markedly diminished in colorectal cancer, precancerous tissues, and a notable portion of normal adjacent tissues (NAT). SiRNA-mediated silencing of AKR1B10 in colon cancer cells HCT-8 enhanced cytotoxicity of acrolein and HNE, whereas ectopic expression of AKR1B10 in colon cancer cells RKO prevented the host cells against carbonyl cytotoxicity. Furthermore, siRNA-mediated AKR1B10 silencing led to DNA breaks and activation of γ-H2AX protein, a marker of DNA double strand breaks, particularly in the exposure of HNE (10 μM). In the AKR1B10 silenced HCT-8 cells, hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutant frequency increased by 26.8 times at basal level and by 33.5 times in the presence of 10 μM HNE when compared to vector control cells. In these cells, the cyclic acrolein-deoxyguanosine adducts levels were increased by over 10 times. These findings were confirmed by pharmacological inhibition of AKR1B10 activity by Epalrestat. Taken together, these data suggest that AKR1B10 is a critical protein that protects host cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 deficiency in the colon may be an important pathogenic factor in disease progression and carcinogenesis. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Clinical Medicine, the First Affiliated Hospital of University of South China, Hengyang, Hunan, China.|Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zu
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Ruilan
authors.initials: R
authors.lastname: Yan
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Jishen
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Cai
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Institute of Clinical Medicine, the First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Fung-Lung
authors.initials: FL
authors.lastname: Chung
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Duan-Fang
authors.initials: DF
authors.lastname: Liao
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.|Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
mesh_terms: D000171:Acrolein / Q000378:metabolism / Q000633:toxicity*; D000449:Aldehyde Reductase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity*; D000074408:Aldo-Keto Reductases; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D012007:Rectum / Q000378:metabolism / Q000473:pathology
chemical_list: D000447:Aldehydes; D009153:Mutagens; D000171:Acrolein; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C027576:4-hydroxy-2-nonenal
keywords: AKR1B10; DNA damage; acrolein-deoxyguanosine adducts; colorectal cancer; electrophilic carbonyl compounds