Contradictory Effects of Mitochondria- and Non-mitochondria-targeted Antioxidants on Hepatocarcinogenesis by Altering DNA Repair

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, it does not fully deny antioxidants for 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. Based on the 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) encouraged tumorigenesis. RNA sequencing revealed that NAC and SS-31 cause highly different changes in oxidation-reduction state and DNA damage response. Remarkably, in diethylnitrosamine (DEN)-treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ATM/ATR for DNA repair while SS-31 and MitoQ aggravated damage by inactivating them. Interestingly, partial recovery of SS-31-scavengened mitochondrial ROS (mtROS) could alleviate SS-31-aggravated DNA damage. Localization of ATM between mitochondria and nuclei was changed after NAC and SS-31 treatment. Furthermore, blockage of p-ATR led to the recurrence of NAC-ameliorated DEN HCC. In contrast, reactivation of p-ATR blocked SS-31-promoted DEN HCC. 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. This article is protected by copyright. All rights reserved.

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