Tian Hui, Gao Zhen, Wang Gang, Li Huizhong, Zheng JunNian
Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiangsu, 221002, People's Republic of China.
Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, 221002, China.
Tumour Biol. 2016 Jan;37(1):141-50. doi: 10.1007/s13277-015-4370-6. Epub 2015 Nov 13.
Estrogen-mediated high reactive oxygen species (ROS) tolerance plays an important role in driving carcinogenesis. ROS overproduction acts as the significant effector to increase genomic instability and transduce redox-related signal pathway. Especially, estrogen-mediated mitochondrial ROS promote the mutations in mitochondrial DNA (mtDNA) and the damage to mitochondrial proteins. Moreover, estrogen-mediated ROS contribute to the alteration of energy metabolism and modulate several redox-sensitive proteins responsible for cell proliferation and anti-apoptosis. On the other hand, estrogen simultaneously performs the antioxidative beneficial functions, which protects cancer cells from the potential cytotoxic effects of estrogen-mediated ROS through activation of nuclear factor-erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) antioxidant response. Consequently, estrogen potentiates the high ROS tolerance through increase of ROS production as well as acceleration of ROS elimination, which ultimately results in estrogen-mediated carcinogenesis and malignant transformation. However, this overdependence on antioxidant response system to resist ROS-mediated cytotoxicity also represents the "Achilles' Heel" of estrogen-mediated cancer cells. In other words, the destruction of the high ROS tolerance using antioxidant inhibitors may provide a novel and efficacious measure to selectively eliminate these cancer cells without harming normal cells. Of course, it will be necessary to define the exact situation of ROS homeostasis in the different cellular microenvironment and further decipher the mechanisms of redox regulation, which is consequently used as a new avenue to optimize the clinical therapy for estrogen-mediated cancer.
雌激素介导的高活性氧（ROS）耐受性在驱动致癌过程中起重要作用。ROS的过度产生是增加基因组不稳定性和转导氧化还原相关信号通路的重要效应因子。特别是，雌激素介导的线粒体ROS促进线粒体DNA（mtDNA）的突变和线粒体蛋白的损伤。此外，雌激素介导的ROS有助于能量代谢的改变，并调节几种负责细胞增殖和抗凋亡的氧化还原敏感蛋白。另一方面，雌激素同时发挥抗氧化有益功能，通过激活核因子红系2相关因子2（Nrf2）/ Kelch样ECH相关蛋白1（Keap1）抗氧化反应，保护癌细胞免受雌激素介导的ROS的潜在细胞毒性作用。因此，雌激素通过增加ROS产生以及加速ROS消除来增强高ROS耐受性，最终导致雌激素介导的致癌作用和恶性转化。然而，这种对抗氧化反应系统抵抗ROS介导的细胞毒性的过度依赖也代表了雌激素介导的癌细胞的“阿喀琉斯之踵”。换句话说，使用抗氧化抑制剂破坏高ROS耐受性可能提供一种新颖且有效的措施来选择性地消除这些癌细胞而不损害正常细胞。当然，有必要确定不同细胞微环境中ROS稳态的确切情况，并进一步破译氧化还原调节机制，从而将其用作优化雌激素介导癌症临床治疗的新途径。
