Aldo‐keto reductase 1B10 protects human colon cells from DNA damage induced by electrophilic carbonyl compounds
Aldo‐keto reductase 1B10 protects human colon cells from DNA damage induced by electrophilic carbonyl compounds
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DOI：
10.1002/mc.22477
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发表时间：
2017-01
影响因子：
4.6
通讯作者：
Xuyu Zu;R. Yan;Jishen Pan;Linlin Zhong;Yu Cao;Jun Ma;Chuan Cai;Dan Huang;Jianghua Liu;F. Chung;D. Liao;D. Cao
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文献类型：
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作者：
Xuyu Zu;R. Yan;Jishen Pan;Linlin Zhong;Yu Cao;Jun Ma;Chuan Cai;Dan Huang;Jianghua Liu;F. Chung;D. Liao;D. Cao
亲电羰基化合物具有高度细胞毒性和遗传毒性。醛酮还原酶 1B10 (AKR1B10) 是一种催化羰基化合物还原为毒性较小的酒精形式的酶。这项研究提供了新的证据，证明 AKR1B10 可以保护结肠细胞免受亲电子羰基化合物诱导的 DNA 损伤。 AKR1B10 在人类结肠上皮细胞中特异性表达，但本研究发现 AKR1B10 表达在结直肠癌、癌前组织和正常邻近组织 (NAT) 的显着部分中丢失或显着减少。结肠癌细胞 HCT-8 中 siRNA 介导的 AKR1B10 沉默增强了丙烯醛和 HNE 的细胞毒性，而结肠癌细胞 RKO 中 AKR1B10 的异位表达则阻止宿主细胞抵抗羰基细胞毒性。此外，siRNA 介导的 AKR1B10 沉默导致 DNA 断裂和 γ-H2AX 蛋白（DNA 双链断裂标记物）的激活，特别是在暴露于 HNE (10 μM) 的情况下。在 AKR1B10 沉默的 HCT-8 细胞中，与载体对照细胞相比，次黄嘌呤鸟嘌呤磷酸核糖转移酶 (HPRT) 突变频率在基础水平增加了 26.8 倍，在 10 μM HNE 存在下增加了 33.5 倍。在这些细胞中，环状丙烯醛-脱氧鸟苷加合物的水平增加了 10 倍以上。这些发现通过依帕司他对 AKR1B10 活性的药理学抑制得到证实。总而言之，这些数据表明 AKR1B10 是一种关键蛋白质，可保护宿主细胞免受亲电羰基化合物诱导的 DNA 损伤。结肠中 AKR1B10 缺陷可能是疾病进展和癌变的重要致病因素。 © 2016 Wiley 期刊公司。
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.