Abstract
The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and associated with tumor malignancy. However, the mechanism of this metabolic switch remains largely unknown. Herein, we reported that hypoxia-inducible factor-1 (HIF-1) induced pyruvate dehydrogenase kinase-3 (PDK3) expression leading to inhibition of mitochondrial respiration. Promoter activity assay, small interference RNA knockdown assay, and chromatin immunoprecipitation assay demonstrated that hypoxia-induced PDK3 gene activity was regulated by HIF-1 at the transcriptional level. Forced expression of PDK3 in cancer cells resulted in increased lactic acid accumulation and drugs resistance, whereas knocking down PDK3 inhibited hypoxia-induced cytoplasmic glycolysis and cell survival. These data demonstrated that increased PDK3 expression due to elevated HIF-1alpha in cancer cells may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy.
Highlights
CoA and NADH to supply the procession of tricarboxylic acid cycle and mitochondrial respiration
Given that pyruvate dehydrogenase kinase-3 (PDK3) is the only pyruvate dehydrogenase kinase (PDK) for which the enzymatic activity is not inhibited by a high concentration of pyruvate, it may play a critical role in causing metabolic switch of cancer cells during progression
Hypoxia Induces PDK3 Expression in Normal and Cancer Cells—To evaluate the expression of PDK3 regulated by HIF, HeLa cells were cultured in 1% O2 or 21% O2 for various times, and expression of PDK3 mRNA was quantified by real-time RT-PCR
Summary
R: 5Ј-GGGCATTCAAAACAAGGAAA-3Ј a The underlining indicates the additional restriction enzyme sites. Units of HIF are more important in regulating gene expression under hypoxia. Previous reports showed that the HIF-␣ subunits are expressed in a tissue-specific manner. Recent data indicate that HIF-2␣ is expressed in numerous other cell types, including kidney fibroblasts, hepatocytes, intestinal epithelial cells, pancreatic interstitial cells, cardiomyocytes, and type II pneumocytes [22, 23]. Given that PDK3 is the only PDK for which the enzymatic activity is not inhibited by a high concentration of pyruvate, it may play a critical role in causing metabolic switch of cancer cells during progression. We aimed to investigate the possible role of HIFs in PDK3 expression and the consequent effect of PDK3 expression in cancer cells. Results from this study provide important information for unraveling the mechanism of cancer malignancy and for considering new anticancer strategy by selecting the novel PDK3 as a molecular target
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