Lai Kun-Goung, Chen Chi-Fen, Ho Chun-Te, Liu Jun-Jen, Liu Tsan-Zon, Chern Chi-Liang
1 Department of Radiation Oncology, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan.
2 Clinical Laboratories, Yuan's General Hospital, Kaohsiung, Taiwan.
Tumour Biol. 2017 Jun;39(6):1010428317702649. doi: 10.1177/1010428317702649.
We provide herein several lines of evidence to substantiate that folic acid (or folate) is a micronutrient capable of functioning as a novel redox regulator on hepatocellular carcinoma. First, we uncovered that folate deficiency could profoundly downregulate two prominent anti-apoptotic effectors including survivin and glucose-regulated protein-78. Silencing of either survivin or glucose-regulated protein-78 via small interfering RNA interfering technique established that both effectors could serve as reactive oxygen species sinker proteins. Second, folate deficiency-triggered oxidative-nitrosative stress could strongly induce endoplasmic reticulum stress that in turn could provoke cellular glutathione depletion through the modulation of the following two crucial events: (1) folate deficiency could strongly inhibit Bcl-2 expression leading to severe suppression of the mitochondrial glutathione pool and (2) folate deficiency could also profoundly inhibit two key enzymes that governing cellular glutathione redox regulation including γ-glutamylcysteinyl synthetase heavy chain, a catalytic enzyme for glutathione biosynthesis, and mitochondrial isocitrate dehydrogenase 2, an enzyme responsible for providing nicotinamide adenine dinucleotide phosphate necessary for regenerating oxidized glutathione disulfide back to glutathione via mitochondrial glutathione reductase. Collectively, we add to the literature new data to strengthen the notion that folate is an essential micronutrient that confers a novel role to combat reactive oxygen species insults and thus serves as a redox regulator via upregulating reactive oxygen species sinker proteins and averting mitochondrial glutathione depletion through proper maintenance of redox homeostasis via positively regulating glutathione biosynthesis, glutathione transporting system, and mitochondrial glutathione recycling process.
我们在此提供了几条证据，以证实叶酸（或叶酸盐）是一种能够作为肝细胞癌新型氧化还原调节剂发挥作用的微量营养素。首先，我们发现叶酸缺乏可显著下调两种突出的抗凋亡效应蛋白，即生存素和葡萄糖调节蛋白78。通过小干扰RNA干扰技术沉默生存素或葡萄糖调节蛋白78，证实这两种效应蛋白均可作为活性氧清除蛋白。其次，叶酸缺乏引发的氧化亚硝化应激可强烈诱导内质网应激，进而通过调节以下两个关键事件导致细胞内谷胱甘肽耗竭：（1）叶酸缺乏可强烈抑制Bcl-2表达，导致线粒体谷胱甘肽池严重受抑；（2）叶酸缺乏还可显著抑制两种控制细胞谷胱甘肽氧化还原调节的关键酶，即γ-谷氨酰半胱氨酸合成酶重链（谷胱甘肽生物合成的催化酶）和线粒体异柠檬酸脱氢酶2（一种负责提供烟酰胺腺嘌呤二核苷酸磷酸的酶，该磷酸通过线粒体谷胱甘肽还原酶将氧化型谷胱甘肽二硫化物再生为谷胱甘肽所必需）。总体而言，我们为文献增添了新数据，以强化叶酸是一种必需微量营养素的观念，它具有对抗活性氧损伤的新作用，从而通过上调活性氧清除蛋白以及通过正向调节谷胱甘肽生物合成、谷胱甘肽转运系统和线粒体谷胱甘肽循环过程来维持氧化还原稳态，避免线粒体谷胱甘肽耗竭，进而作为一种氧化还原调节剂发挥作用。
