己糖激酶II通过磷酸化丙酮酸脱氢酶的α亚基来促进瓦伯格效应。
Hexokinase II promotes the Warburg effect by phosphorylating alpha subunit of pyruvate dehydrogenase.
作者信息
Luo Fangxiu, Li You, Yuan Fei, Zuo Junli
机构信息
Department of Pathology, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, Shanghai 201801, China.
Department of General Surgery, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, Shanghai 201801, China.
出版信息
Chin J Cancer Res. 2019 Jun;31(3):521-532. doi: 10.21147/j.issn.1000-9604.2019.03.14.
OBJECTIVE
Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II (HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells.
METHODS
HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase (PDHA1) was tested in HEK293T cells and clear cell renal cell carcinoma (ccRCC) specimens using gene knockdown, western blotting, immunohistochemistry, and immunofluorescence.
RESULTS
It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase (PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in ccRCC.
CONCLUSIONS
The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.
目的
肿瘤细胞无论氧分压如何，都严重依赖糖酵解，这种现象称为瓦伯格效应。己糖激酶II（HKII）催化糖酵解的第一步不可逆反应，且在肿瘤细胞中常过度表达。线粒体HKII将糖酵解与氧化磷酸化偶联，同时维持线粒体膜的完整性。在本研究中，我们探究了HKII在促进癌细胞瓦伯格效应中的作用。
方法
在HEK293T细胞和透明细胞肾细胞癌（ccRCC）标本中，采用基因敲低、蛋白质印迹法、免疫组织化学和免疫荧光法检测HKII介导的丙酮酸脱氢酶α亚基（PDHA1）的磷酸化。
结果
确定HKII不仅能将葡萄糖转化为6-磷酸葡萄糖，还能将ATP的磷酸基团转移到PDHA1上。此外，发现HKII增加了PDHA1上Ser293的磷酸化，降低了丙酮酸脱氢酶（PDH）复合物的活性，从而改变代谢途径并促进瓦伯格效应。HKII的过表达与ccRCC中PDHA1的磷酸化及疾病进展相关。
结论
此处呈现的数据表明，HKII是癌症评估和治疗中的重要生物标志物。
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