Imbalance in Protein Thiol Redox Regulation and Cancer-Preventive Efficacy of Selenium.
Imbalance in Protein Thiol Redox Regulation and Cancer-Preventive Efficacy of Selenium.
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DOI：
10.20455/ros.2016.851
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Holmgren A
中科院分区：
文献类型：
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作者：
Gopalakrishna R;Gundimeda U;Zhou S;Zung K;Forell K;Holmgren A
虽然一些实验研究表明，膳食补充硒具有预防癌症的功效，但人体临床试验对这种功效提出了质疑。确定其分子靶点和机制对于理解这种差异非常重要。硒的活性代谢产物甲基硒醇与蛋白激酶C（PKC）结合的脂质过氧化氢反应并氧化为甲基硒酸（MSA）。这种局部产生的MSA通过氧化其关键的半胱氨酸巯基选择性地使PKC失活。在这个过程中发生的过氧化物氧化还原循环可以解释如何极低浓度的硒催化修饰特定的膜结合蛋白隔室分离谷胱甘肽和选择性诱导细胞毒性促进细胞。哺乳动物硫氧还蛋白还原酶（TR）本身是一种硒酶，具有催化硒代半胱氨酸残基。它与硫氧还蛋白（Trx）一起催化NADPH还原亚硒酸盐和硒代胱氨酸生成硒化物，硒化物在氧氧化还原循环的存在下产生活性氧。Trx以高亲和力与PKC结合并逆转PKC失活。因此，建立过表达TR和Trx的肿瘤细胞可能会逃避硒的癌症预防作用。这表明，在某些情况下，某些硒蛋白可能会抵消硒代谢作用。低浓度的硒容易抑制抗凋亡PKC同工酶e和a，它们具有一簇相邻的巯基，从而诱导细胞凋亡。高浓度的硒也抑制促凋亡酶，如蛋白水解激活的PKCd片段、holo-PKCz、caspase-3和c-Jun N-末端激酶，它们都具有有限数量的关键半胱氨酸残基，使肿瘤细胞对硒诱导的凋亡具有抗性。这可以解释膳食硒摄入量和癌症预防程度之间有趣的U形曲线。
Although several experimental studies showed cancer-preventive efficacy of supplemental dietary selenium, human clinical trials questioned this efficacy. Identifying its molecular targets and mechanism is important in understanding this discrepancy. Methylselenol, the active metabolite of selenium, reacts with lipid hydroperoxides bound to protein kinase C (PKC) and is oxidized to methylseleninic acid (MSA). This locally generated MSA selectively inactivates PKC by oxidizing its critical cysteine sulfhydryls. The peroxidatic redox cycle occurring in this process may explain how extremely low concentrations of selenium catalytically modify specific membrane-bound proteins compartmentally separated from glutathione and selectively induce cytotoxicity in promoting cells. Mammalian thioredoxin reductase (TR) is itself a selenoenzyme with a catalytic selenocysteine residue. Together with thioredoxin (Trx), it catalyzes reduction of selenite and selenocystine by NADPH generating selenide which in the presence of oxygen redox cycles producing reactive oxygen species. Trx binds with high affinity to PKC and reverses PKC inactivation. Therefore, established tumor cells overexpressing TR and Trx may escape the cancer-preventive actions of selenium. This suggests that in some cases, certain selenoproteins may counteract selenometabolite actions. Lower concentrations of selenium readily inactivate antiapoptotic PKC isoenzymes e and a which have a cluster of vicinal thiols, thereby inducing apoptosis. Higher concentrations of selenium also inactivate proapoptotic enzymes such as proteolytically activated PKCd fragment, holo-PKCz, caspase-3, and c-Jun N-terminal kinase, which all have a limited number of critical cysteine residues and make tumor cells resistant to selenium-induced apoptosis. This may explain the intriguing U-shaped curve that is seen with dietary selenium intake and the extent of cancer prevention.