Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells
Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells
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DOI：
10.1074/jbc.m801765200
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发表时间：
2008-08-15
影响因子：
4.8
通讯作者：
Verma, Ajay
中科院分区：
文献类型：
--
作者：
McFate, Thomas;Mohyeldin, Ahmed;Verma, Ajay
尽管氧气条件正常，但癌细胞和肿瘤中常见高乳酸产生和低葡萄糖氧化。这种改变的代谢表型在历史上被称为瓦尔堡效应，长期以来一直与恶性进展和不良临床结局相关。然而，糖代谢改变和恶性肿瘤之间的机制关系仍然知之甚少。在这里，我们表明，丙酮酸脱氢酶复合物（PDC）活性的抑制有助于瓦尔堡代谢和恶性表型在人头颈部鳞状细胞癌。PDC抑制通过丙酮酸脱氢酶激酶-1（PDK-1）的增强表达发生，这导致丙酮酸脱氢酶α（PDH α）亚基的抑制性磷酸化。我们还证明，PDC抑制癌细胞与正常氧稳定的恶性促进转录因子缺氧诱导因子-1 α（HIF-1 α）的糖酵解代谢产物。通过短发夹RNA敲低PDK-1可降低PDH α磷酸化，恢复PDC活性，逆转瓦尔堡代谢表型，降低常氧HIF-1 α表达，降低缺氧细胞存活率，降低侵袭性，并抑制肿瘤生长。PDK-1是一个HIF-1调节基因，这些数据表明，糖酵解代谢产物的积累，导致高PDK-1表达，可能反过来促进HIF-1激活，从而维持恶性进展的前馈回路。除了为癌细胞提供合成代谢支持外，改变的燃料代谢因此支持恶性表型。代谢异常的纠正为癌症治疗提供了独特的机会，并可能与其他癌症疗法协同作用。
High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase alpha(PDH alpha) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1 alpha(HIF-1 alpha) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDH alpha phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1 alpha expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.