Bibo Wang1, Jing Fu1,2, Ting Yu1,3, An Xu1, Wenhao Qin1, Zhishi Yang1, Yao Chen1,2, Hongyang Wang1,2. 1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. 2. National Center for Liver Cancer, Shanghai, China. 3. Fuling Central Hospital of Chongqing City, Chongqing, China.
Abstract
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 non-mitochondrial- and mitochondrial-targeted antioxidants. Utilizing mouse models of chemical hepatocarcinogenesis, we showed that administration of non-mitochondria-targeted antioxidants N-acetylcysteine (NAC) and the soluble vitamin E analog, Trolox, prevented tumorigenesis, whereas administration of mitochondria-targeted antioxidants SS-31 (the mitochondria-targeted peptide) and Mito-Q (a derivative of ubiquinone) facilitated tumorigenesis. RNA sequencing revealed that NAC and SS-31 caused very different changes in the oxidation-reduction state and DNA damage response. In diethylnitrosamine (DEN)-treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ataxia-telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) for DNA repair whereas SS-31 and Mito-Q aggravated damage by inactivating them. Interestingly, partial recovery of SS-31-scavengened mitochondrial reactive oxygen species (mtROS) could alleviate SS-31-aggravated DNA damage. Localization of ATM between mitochondria and nuclei was altered after NAC and SS-31 treatment. Furthermore, blockage of phospho-ATR (p-ATR) led to the recurrence of NAC-ameliorated DEN HCC. In contrast, reactivation of p-ATR blocked SS-31-promoted 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;67:623-635).
Conflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancerpatients. 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 non-mitochondrial- and mitochondrial-targeted antioxidants. Utilizing mouse models of chemical hepatocarcinogenesis, we showed that administration of non-mitochondria-targeted antioxidants N-acetylcysteine (NAC) and the soluble vitamin E analog, Trolox, prevented tumorigenesis, whereas administration of mitochondria-targeted antioxidants SS-31 (the mitochondria-targeted peptide) and Mito-Q (a derivative of ubiquinone) facilitated tumorigenesis. RNA sequencing revealed that NAC and SS-31 caused very different changes in the oxidation-reduction state and DNA damage response. In diethylnitrosamine (DEN)-treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ataxia-telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) for DNA repair whereas SS-31 and Mito-Q aggravated damage by inactivating them. Interestingly, partial recovery of SS-31-scavengened mitochondrial reactive oxygen species (mtROS) could alleviate SS-31-aggravated DNA damage. Localization of ATM between mitochondria and nuclei was altered after NAC and SS-31 treatment. Furthermore, blockage of phospho-ATR (p-ATR) led to the recurrence of NAC-ameliorated DEN HCC. In contrast, reactivation of p-ATR blocked SS-31-promoted 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;67:623-635).
Authors: Kristell Le Gal; Clotilde Wiel; Mohamed X Ibrahim; Marcus Henricsson; Volkan I Sayin; Martin O Bergo Journal: Antioxidants (Basel) Date: 2021-01-22