Contradictory Effects of Mitochondria- and Non-mitochondria-targeted Antioxidants on Hepatocarcinogenesis by Altering DNA Repair
Contradictory Effects of Mitochondria- and Non-mitochondria-targeted Antioxidants on Hepatocarcinogenesis by Altering DNA Repair
复制标题
线粒体和非线粒体靶向抗氧化剂通过改变 DNA 修复对肝癌发生的矛盾作用
作者：
王碧波;付静;余挺;徐安;秦文昊;杨知时;陈瑶;王红阳
抗氧化剂补充剂对癌症预防或促进的抑制作用是健康人和癌症患者非常关注的。尽管最近的研究表明抗氧化剂会加速肺癌和黑色素瘤的进展，但抗氧化剂仍可能在癌症预防中发挥作用。肿瘤和抗氧化剂类型都会影响实际疗效。然而，人们对不同类型的抗氧化剂对原发性肝细胞癌（HCC）的影响知之甚少，包括非线粒体和线粒体靶向抗氧化剂。利用化学性肝癌发生的小鼠模型，我们发现给予非线粒体靶向抗氧化剂N-乙酰半胱氨酸（NAC）和可溶性维生素E类似物Trolox可预防肿瘤发生，而给予线粒体靶向抗氧化剂SS-31（线粒体靶向肽）和Mito-Q（泛醌衍生物）可促进肿瘤发生。RNA测序显示，NAC和SS-31引起氧化还原状态和DNA损伤反应的变化非常不同。在二乙基亚硝胺（DEN）处理的原代肝细胞中，NAC和Trolox通过激活共济失调毛细血管扩张突变（ATM）/ATM和Rad 3相关（ATR）进行DNA修复来减轻DNA损伤，而SS-31和Mito-Q通过灭活它们来加重损伤。有趣的是，SS-31清除的线粒体活性氧（mtROS）的部分恢复可以减轻SS-31加重的DNA损伤。在NAC和SS-31处理后，线粒体和细胞核之间的ATM定位发生改变。此外，磷酸化ATR（p-ATR）的阻断导致NAC改善的DEN HCC复发。相反，p-ATR的再激活阻断SS-31-促进DEN HCC.Conclusion：这些结果表明，抗氧化剂的类型在肝癌发生中起着以前未被认识到的作用，并为探索抗氧化剂用于肝癌的治疗提供了一种机制。（肝脏病学2018;67：623 - 635）。
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 antioxidantsN‐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. (Hepatology2018;67:623‐635).