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.

Identification of key tumorigenesis‑related genes and their microRNAs in colon cancer

“…In order to further understand CRC, we innovatively and exclusively focused on the 10 hub genes and two miRNAs, hsa-let-7g and hsa-let-7f-1. SPARC, CA4, CXCL3, FABP1, CLDN2, AKR1B10 and FXYD3 have previously been reported as genes that are tightly involved in the development of CRC (19)(20)(21)(22)(23)(24)(25)(26). COL9A3, CHGA, and TRPM6 have been rarely studied and reported, but which may provide novel insight into the research of CRC.…”

Opposing roles of the aldo-keto reductases AKR1B1 and AKR1B10 in colorectal cancer

“…Overexpression of AKR1B10 in HCT-116 cells did not result in any alteration in proliferation, apoptosis or cell cycle progression. AKR1B10 has been reported to metabolize cytotoxic carbonyl compounds to harmless intermediates [16]. Loss of AKR1B10 expression in CRC tissues may hamper the protection of these tissues from DNA damage by carbonyl compounds.…”

“…Additionally, AKR1B10 has been reported to serve as a direct transcriptional target of p53 and to participate in p53mediated apoptosis [15]. AKR1B10 can also metabolize electrophilic carbonyl compounds to harmless intermediates and, thereby, protect CRC cells from DNA damage [16].…”

A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

“…AKR1B10 is a secretory protein up-regulated in HCC. (14)(15)(16) AKR1B10 can eliminate cytotoxic and carcinogenic α and β-unsaturated carbonyl compounds (17)(18)(19)(20)(21) and regulate de novo fatty acid/lipid synthesis. (22)(23)(24) In normal tissues, AKR1B10 is specifically expressed in the colon and small intestine, where it is secreted into the lumen.…”