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Contradictory effects of mitochondria and nonmitochondriatargeted antioxidants on hepatocarcinogenesis by altering DNA repair in mice

Author：Bibo Wang. Jing Fu. Ting Yu, An Xu, Wenhao Qin, Zhishi Yang, Yao Chen, Hongyang Wang   《HEPATOLOGY》

ABSTRACTS
Conflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancer patients. Despite recent studies about antioxidants accelerating the progression of lung cancer and melanoma, antioxidants may still play a role in cancer prevention. Both tumor and antioxidants types influence the actual efficacy. However, little is known about the impact of different types of antioxidants on primary hepatocellular carcinoma (HCC), including nonmitochondrial and mitochondrialtargeted antioxidants. Utilizing mouse models of chemical hepatocarcinogenesis, we showed that administration of nonmitochondriatargeted antioxidants Nacetylcysteine (NAC) and the soluble vitamin E analog, Trolox, prevented tumorigenesis, whereas administration of mitochondriatargeted antioxidants SS31 (the mitochondriatargeted peptide) and MitoQ (a derivative of ubiquinone) facilitated tumorigenesis. RNA sequencing revealed that NAC and SS31 caused very different changes in the oxidationreduction state and DNA damage response. In diethylnitrosamine (DEN)treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ataxiatelangiectasia mutated (ATM)/ATM and Rad3related (ATR) for DNA repair whereas SS31 and MitoQ aggravated damage by inactivating them. Interestingly, partial recovery of SS31scavengened mitochondrial reactive oxygen species (mtROS) could alleviate SS31aggravated DNA damage. Localization of ATM between mitochondria and nuclei was altered after NAC and SS31 treatment. Furthermore, blockage of phosphoATR (pATR) led to the recurrence of NACameliorated DEN HCC. In contrast, reactivation of pATR blocked SS31promoted DEN HCC. Conclusion: These results demonstrate that the type of antioxidants plays a previously unappreciated role in hepatocarcinogenesis, and provide a mechanistic rationale for exploring the therapeutic use of antioxidants for liver cancer. (Hepatology 2018;67:623635).
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SS-31 (r-2″, 6″-DEN-KF-NH2; ChinaPeptides Co.) 
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https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.29518
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