Regulation of pyruvate dehydrogenase kinase by hypoxia and its impact on drug resistance in cancer cells
| Autor: | Chun-wun Lu, 呂淳雯 |
|---|---|
| Rok vydání: | 2009 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 97 The switch of cellular metabolism from mitochondrial respiration to cytoplasmic glycolysis is critical for the adaptation to hypoxia in tumor cells. However, the mechanism of this metabolic switch remains largely unknown. Pyruvate dehydrogenase kinase (PDK) is the enzyme that blocks tricarboxylic acid (TCA) cycle initiation by inactivating pyruvate dehydrogenase (PDH). We hypothesize that hypoxia may upregulate PDK, which in turn inactivates PDH and blocks the entry of TCA cycle. Here, we reported that the expressions of PDK1 and PDK3 were increased in several cancer cell lines, such as HeLa and colorectal cancer cell lines under hypoxia. Promoter activity assay demonstrated that hypoxia elevated PDK1 and PDK3 promoter activities and this effect was abolished by mutation of hypoxia response element. Chemical-mimicked hypoxia also induced the promoter activity and expression of PDK3. In addition, siRNA and chromatin immunoprecipitation assay provided further evidence that increased expression of PDK3 was mediated by HIF-1α. Forced expression of PDK3 in cancer cells resulted in increased lactic acid accumulation and drug resistance, whereas PDK3 knockdown inhibited hypoxia-induced cytoplasmic glycolysis and cell survival. Moreover, PDK3 expression was elevated in cervical cancer and colorectal cancer tissues. The level of PDK3 was correlated with the HIF-1α expression in colorectal cancer tissues. These data demonstrated that increased PDK3 expression due to elevated HIF-1α in cancer may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy |
| Databáze: | Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
|