Induction of Pyruvate Dehydrogenase Kinase-3 by Hypoxia-inducible Factor-1 Promotes Metabolic Switch and Drug Resistance

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-1α in cancer cells may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy. 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-1α in cancer cells may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy. Elevated glucose uptake and the switch of cellular metabolism from oxidative phosphorylation to aerobic glycolysis are hallmarks of cancer cells, a phenomenon known as the Warburg effect (1Warburg, O., Wind, F., and Neglers, E. (1930) The Metabolism of Tumors Constable and Co., London, pp. 254–270Google Scholar). It is considered that Warburg effect is a critical cellular metabolic adaptation to overexpression of hypoxia-inducible factor (HIF) 2The abbreviations used are: HIF, hypoxia-inducible factor; E1, pyruvate dehydrogenase; E2, dihydrolipoyl acetyltransferase; E3, dihydrolipoyl dehydrogenase; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; DMOG, dimethyloxaloylglycine; DFO, desferrioxamine; RT, reverse transcription; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; HRE, binding element of HIF; siRNA, short interference RNA. in cancer cells, and elevated glycolysis is due to increased expression of genes encoding glucose transporters and glycolytic enzymes induced by HIF-1 (2Iyer N.V. Kotch L.E. Agani F. Leung S.W. Laughner E. Wenger R.H. Gassmann M. Gearhart J.D. Lawler A.M. Yu A.Y. Semenza G.L. Genes Dev. 1998; 12: 149-162Crossref PubMed Scopus (2051) Google Scholar, 3Seagroves T.N. Ryan H.E. Lu H. Wouters B.G. Knapp M. Thibault P. Laderoute K. Johnson R.S. Mol. Cell. Biol. 2001; 21: 3436-3444Crossref PubMed Scopus (480) Google Scholar, 4Greijer A.E. van der Groep P. Kemming D. Shvarts A. Semenza G.L. Meijer G.A. van de Wiel M.A. Belien J.A. van Diest P.J. van der Wall E. J. Pathol. 2005; 206: 291-304Crossref PubMed Scopus (361) Google Scholar). However, how cells switch metabolism from oxidative phosphorylation to aerobic glycolysis is still unclear. Pyruvate dehydrogenase complex is responsible for catalyzing oxidative decarboxylation of pyruvate to produce acetylCoA and NADH to supply the procession of tricarboxylic acid cycle (also known as Krebs cycle) and mitochondrial respiration. Pyruvate dehydrogenase complex is a multienzyme complex consisting of three catalytic enzymes, E1, E2, and E3 (5Patel M.S. Korotchkina L.G. Exp. Mol. Med. 2001; 33: 191-197Crossref PubMed Scopus (126) Google Scholar). The E1 enzyme is also known as pyruvate dehydrogenase (PDH), which catalyzes the rate-limiting reaction of converting pyruvate to acetyl-CoA. The activity of PDH is primarily regulated by pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase. PDK phosphorylates the α-subunit of PDH to suppress its enzymatic activity, whereas pyruvate dehydrogenase phosphatase dephosphorylates and thus activates PDH (5Patel M.S. Korotchkina L.G. Exp. Mol. Med. 2001; 33: 191-197Crossref PubMed Scopus (126) Google Scholar, 6Roche T.E. Hiromasa Y. Cell Mol. Life Sci. 2007; 64: 830-849Crossref PubMed Scopus (191) Google Scholar). Four isotypes of PDKs (PDK1–4), encoded by distinct genes, have been identified in mammals. The expression levels of PDKs vary in a tissue-specific manner, suggesting that they may have different functions (7Bowker-Kinley M.M. Davis W.I. Wu P. Harris R.A. Popov K.M. Biochem. J. 1998; 329: 191-196Crossref PubMed Scopus (447) Google Scholar, 8Gudi R. Bowker-Kinley M.M. Kedishvili N.Y. Zhao Y. Popov K.M. J. Biol. Chem. 1995; 270: 28989-28994Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). In addition, the kinetic parameters and regulation of PDKs are also different among different isogenes. The expression of PDK1 can be up-regulated by hypoxia (9Kim J.W. Tchernyshyov I. Semenza G.L. Dang C.V. Cell Metab. 2006; 3: 177-185Abstract Full Text Full Text PDF PubMed Scopus (2608) Google Scholar, 10Papandreou I. Cairns R.A. Fontana L. Lim A.L. Denko N.C. Cell Metab. 2006; 3: 187-197Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar), whereas the expression of PDK2 is elevated in liver, kidney, and mammary gland during starvation (11Wu P. Blair P.V. Sato J. Jaskiewicz J. Popov K.M. Harris R.A. Arch. Biochem. Biophys. 2000; 381: 1-7Crossref PubMed Scopus (152) Google Scholar). High fat diet and diabetes can enhance PDK4 expression (12Holness M.J. Kraus A. Harris R.A. Sugden M.C. Diabetes. 2000; 49: 775-781Crossref PubMed Scopus (144) Google Scholar, 13Wu P. Inskeep K. Bowker-Kinley M.M. Popov K.M. Harris R.A. Diabetes. 1999; 48: 1593-1599Crossref PubMed Scopus (240) Google Scholar). However, the regulation of PDK3 gene expression was never reported before. The activity of PDKs is largely determined by the binding capacity of PDKs to the lipoyl domain of E2. The binding affinity of PDK3 to E2 is the greatest (relative order: PDK3 > PDK1 = PDK2 > PDK4) (14Tuganova A. Boulatnikov I. Popov K.M. Biochem. J. 2002; 366: 129-136Crossref PubMed Google Scholar); therefore, it is not surprising that the enzyme activity of PDK3 is the highest among all PDKs (25-fold higher than the activity of the least active PDK2) (7Bowker-Kinley M.M. Davis W.I. Wu P. Harris R.A. Popov K.M. Biochem. J. 1998; 329: 191-196Crossref PubMed Scopus (447) Google Scholar). Furthermore, high concentration of pyruvate inhibits the activity of PDK1, -2, and -4, but not PDK3 (7Bowker-Kinley M.M. Davis W.I. Wu P. Harris R.A. Popov K.M. Biochem. J. 1998; 329: 191-196Crossref PubMed Scopus (447) Google Scholar, 15Baker J.C. Yan X. Peng T. Kasten S. Roche T.E. J. Biol. Chem. 2000; 275: 15773-15781Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). This unique feature implicates the potential importance of PDK3 in the metabolic switch of cancer cells and makes it the most prominent new candidate as a target for cancer therapy. When the size of solid tumor is greater than 1 mm3, cells will face hypoxic stress due to slow growth of blood vessels (16Brown J.M. Giaccia A.J. Cancer Res. 1998; 58: 1408-1416PubMed Google Scholar). One of cell's responses to hypoxia is through the HIF-regulated gene expression to modulate several biological processes such as angiogenesis, proliferation, migration, apoptosis, and metabolism (17Ke Q. Costa M. Mol. Pharmacol. 2006; 70: 1469-1480Crossref PubMed Scopus (1219) Google Scholar). HIF is a heterodimeric transcription factor consisting of the α (HIF-1α, HIF-2α or HIF-3α) and β subunits (18Semenza G. Biochem. Pharmacol. 2002; 64: 993-998Crossref PubMed Scopus (747) Google Scholar). HIF-1β, also known as aryl hydrocarbon receptor nuclear translocator, is constitutively expressed, whereas the protein of HIF-α is inducible under hypoxia (18Semenza G. Biochem. Pharmacol. 2002; 64: 993-998Crossref PubMed Scopus (747) Google Scholar). Therefore, the α subunits of HIF are more important in regulating gene expression under hypoxia. Previous reports showed that the HIF-α subunits are expressed in a tissue-specific manner. HIF-1α is expressed ubiquitously in human tissues, whereas HIF-2α is expressed in restricted tissues such as lung, endothelium, and carotid body (19Ema M. Taya S. Yokotani N. Sogawa K. Matsuda Y. Fujii-Kuriyama Y. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4273-4278Crossref PubMed Scopus (844) Google Scholar, 20Tian H. Hammer R.E. Matsumoto A.M. 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To date, accumulating evidence shows that HIF-1α and HIF-2α are involved in tumor progression, whereas the expression and function of HIF-3α remain uncharacterized (17Ke Q. Costa M. Mol. Pharmacol. 2006; 70: 1469-1480Crossref PubMed Scopus (1219) Google Scholar, 24Holmquist-Mengelbier L. Fredlund E. Lofstedt T. Noguera R. Navarro S. Nilsson H. Pietras A. Vallon-Christersson J. Borg A. Gradin K. Poellinger L. Pahlman S. Cancer Cell. 2006; 10: 413-423Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 25Haase V.H. Am. J. Physiol. 2006; 291: F271-F281Crossref PubMed Scopus (265) Google Scholar). 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. Therefore, 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. Cell Culture and Hypoxia Treatment—Cell lines, including HeLa, IMR32, and colo320DM, were maintained in specific culture media recommended by the American Type Culture Collection and were supplemented with 10% fetal bovine serum. The human endometrial stromal cells were purified and cultured in Dulbecco's modified Eagle's medium/F-12 medium with 10% fetal bovine serum, as previously described (26Tsai S.J. Wu 2002; PubMed Scopus Google Scholar, S.J. Wu J. Metab. 2001; PubMed Scopus Google Scholar). and cells were at a of cells The medium was at 1 to of and growth was in with and or with or RNA and RNA was from cells to the RNA and were determined at and RNA was to reverse transcription at for by a as previously described S.J. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar). The used in this study are in 1 the which was reported previously Wu S.J. 2003; PubMed Scopus Google of used in this the enzyme of reverse of of reverse of PDK3 reverse PDK3 reverse The the enzyme of reverse of of reverse of PDK3 reverse PDK3 reverse in a new of were by and to a which was with and with specific and with was the Life The were with and and with different used in this study are: and and Promoter of human were from the data were with of by human were to the to human PDK3 were and of the was by the with cells were for a were the cells the cells were in 10% fetal bovine Dulbecco's modified Eagle's medium/F-12 medium for The medium was and cells were to or hypoxic for were the to the of was to of and activity was a The of was determined by assay was in and as in the used was as described S.J. Res. 2005; 33: PubMed Scopus Google Scholar, C.W. S.J. Am. J. Pathol. 2007; Full Text Full Text PDF PubMed Scopus Google with In and in or cells were by for at with a concentration of of the the cells were with and a was to of by the cell of the was for The chromatin was with bovine and protein or was to the and to chromatin immunoprecipitation assay from was by specific interference human PDK1, and were from The was used to cells with a concentration of cells were in or hypoxia for and to or as described In a cells were to as described of was determined by of gene A.J. S. A. A.L. R. 2003; PubMed Scopus Google of used in this in a new of and Cell were cultured under or hypoxia for were for of lactic acid a to the recommended by the were by for three and under by In used and were to culture medium to or hypoxia cells were by a to the were by at for and by at for were with at for for by with at for by terminal deoxynucleotidyl at for cells were with reaction to the of with and by at for The reaction was by the cells with at for the cells by the cells were with at for to the The was by reaction to at the of at least cells were to the of data are expressed as of the were of in was used to the In was used to was at Hypoxia PDK3 in and Cancer the expression of PDK3 regulated by HIF, cells were cultured in or for and expression of PDK3 was by Hypoxia up-regulated HIF-1α and HIF-2α in cells, whereas the constitutively expressed was not of PDK3 was up-regulated at and hypoxia the of PDK3 protein was also elevated To investigate the role of HIF in PDK3 DFO, that HIF-1α and the DMOG, were used to HIF-1α HIF-2α and levels of PDK3 were with and induced PDK3 expression and induced PDK3 protein by increased HIF-1α and HIF-2α accumulation in the cell These demonstrated that hypoxia-induced PDK1 and PDK3 expression was by HIF-1α we elevated expression of PDK3 by hypoxia was a among different cell The cancer cell IMR32, cancer cell colo320DM, and cultured human endometrial stromal cells were under or hypoxia as described to the in cells, hypoxia induced PDK3 gene expression in three of cells This demonstrated that of PDK3 under hypoxia is a in and cancer cells. of PDK3 by Hypoxia through but HIF-1α and HIF-2α were up-regulated under hypoxia we aimed to expression of PDK3 by hypoxia was regulated by or of human HIF-1α and were used to down the HIF-1α HIF-2α to this the and of and data not HIF-1α and HIF-2α knockdown cells were cultured under hypoxia and the expression of PDK3 was by of PDK3 was increased in cells with under hypoxia. down HIF-1α inhibited hypoxia-induced PDK3 expression the other the hypoxia-induced PDK3 expression was not by knocking down whereas knockdown of HIF-1α and HIF-2α a effect as that by knockdown of HIF-1α These demonstrated that hypoxia the expression of PDK3 HIF-1α but not by PDK3 at the investigate of HIF the expression of PDK3 and molecular of such we a to the of possible binding of HIF in the of human PDK3 is at of human PDK3 To the was of PDK3 was and activity was The activity of PDK3 was increased in hypoxia cells The also that are in the human PDK1 with a in human PDK2 and in human PDK4 In with the activity of PDK1 was increased under hypoxia whereas the of PDK2 and PDK4 were not by hypoxia and To that hypoxia-induced in PDK3 and PDK1 were by the of were to HIF-1 binding of the in PDK3 activity under hypoxia of inhibited hypoxia-induced PDK1 activity, whereas of in PDK1 only PDK1 activity with increased the of PDK3 and PDK1, whereas PDK2 activity was not by The was with the of in the PDK The with higher in PDK3 and in was more whereas the with in PDK1 and in PDK2) or to hypoxia. we the was to the PDK3 under hypoxia. or three of PDK3 and were cells, and activity was determined of cells with the activity the of activity in cells with was greater than that in cells with only the and cells were with DFO, the demonstrated that of PDK3 was by binding of HIF transcription factor to the and that the was for PDK3 The binding of HIF-1α to the of PDK3 was by chromatin immunoprecipitation and the we HIF-1α to the of PDK3 in cells with or hypoxia In at a of the transcription to PDK3 in HIF-1α These the evidence to the binding of HIF-1α to the PDK3 the cells. of PDK3 phosphorylation of PDH by PDK will switch the glucose metabolism from mitochondrial respiration to cytoplasmic glycolysis and in accumulation of lactic thus the of lactic acid to the role of of PDK3 were used to down the expression of of and the cellular levels of PDK3 and whereas the effect of lactic acid induced by hypoxia was inhibited in cells To the role of PDK3 in lactic acid encoding human PDK3 was Forced expression of PDK3 increased lactic acid under and These data demonstrated that PDK3 was and for the of metabolic of PDK3 under Hypoxia Cell is known that cancer cells with increased lactic acid due to metabolic switch are more to thus aimed to of PDK3 by HIF-1α play a role in increased used and were for of cancer cells under However, cultured under hypoxia the of cells by was were also was used To that increased under hypoxia was by of we down PDK3 in cells and cell Results demonstrated that knocking down PDK3 not cell under whereas the of cells was under hypoxia Furthermore, increased to was in PDK3 knockdown cells Results from assay demonstrated that knocking down PDK3 increased the of cells and suggesting that the cell was due to increased cell the other overexpression of PDK3 cell or under and demonstrated that of PDK3 a role in hypoxia-induced of PDK1 and PDK3 by HIF PDK1 and PDK3 were up-regulated under hypoxia we were to the roles of of cell with PDK1 PDK1 expression to was in PDK3 knockdown cells, of PDK1 resulted in increased cell under hypoxia knockdown of PDK1 and PDK3 more cell under hypoxia suggesting effect cell survival. When cells were with or cells of cell with cells knockdown PDK1 and PDK3 resulted in to data provide evidence to that PDK1 and PDK3 effect in glucose uptake and aerobic glycolysis are hallmarks of of cancer cells. the cellular metabolism from mitochondrial respiration to cytoplasmic glycolysis not only a for adaptation to hypoxia but also a for cell and However, how this metabolic switch is remains and thus of PDH by PDK the of pyruvate to and the of mitochondrial respiration. and molecular biological we demonstrated that expression of PDK3 is induced by HIF-1α and that of PDK3 is critical in metabolic switch and in cancer cells Warburg that cancer cells more glucose than cells, and the cancer cells is through of pyruvate to lactic acid under a known as aerobic glycolysis or the Warburg effect (1Warburg, O., Wind, F., and Neglers, E. (1930) The Metabolism of Tumors Constable and Co., London, pp. 254–270Google Scholar). the mechanism of Warburg effect was known of glycolytic enzymes by HIF was identified (9Kim J.W. Tchernyshyov I. Semenza G.L. Dang C.V. Cell Metab. 2006; 3: 177-185Abstract Full Text Full Text PDF PubMed Scopus (2608) Google Scholar, 10Papandreou I. Cairns R.A. Fontana L. Lim A.L. Denko N.C. Cell Metab. 2006; 3: 187-197Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar, J. P. Cancer Cell. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). In the glucose metabolic PDK inhibits the of pyruvate to thus the to the Krebs cycle by phosphorylation and of of PDKs inhibits mitochondrial respiration and the cellular to cytoplasmic the PDK we demonstrated that hypoxia can PDK1 and PDK3 but not PDK2 or PDK4 The of of PDK2 by hypoxia was different from in cells S. S.L. J. A. C. R. L. S. G. K. M.A. Cancer Cell. 2007; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). The is not known but may be due to in cell we the binding of HIF-1α PDK3 by and we that HIF-1α was for PDK3 HIF-2α not to of data provide evidence to distinct functions of HIF-1α and HIF-2α and in PDK3 is under hypoxia or HIF-1α how HIF-1α mitochondrial respiration to cytoplasmic glycolysis is not In this we demonstrated that of PDK3 under hypoxia-induced HIF-1α accumulation in increased lactic acid mitochondrial respiration is inhibited and cytoplasmic glycolysis is demonstrated that expression of PDK3 is to lactic acid under whereas down PDK3 expression inhibited hypoxia-induced lactic acid These data provide evidence to important of the mechanism of metabolic switch under hypoxia body of evidence that overexpression of HIF-1α is to in human and is associated with and H. A.M. Laughner E. Lim M. D. P. Semenza G.L. J.W. Cancer Res. 1999; Google Scholar). study demonstrated that mitochondrial cells have a H. R.H. M. L. R. J.S. Y. L. L. M.J. P. J. Cell Biol. 2006; PubMed Scopus Google Scholar). In cells, of PDK1 and PDK3 thus mitochondrial respiration may also in this study we demonstrated that hypoxic cells are more to cell However, the under hypoxia was PDK3 was by In overexpression of PDK3 was to under These data demonstrated that metabolic switch important roles in hypoxia-induced increased to drugs and a molecular mechanism to at least in the of in hypoxic it was reported that PDK1 is also induced by hypoxia (9Kim J.W. Tchernyshyov I. Semenza G.L. Dang C.V. Cell Metab. 2006; 3: 177-185Abstract Full Text Full Text PDF PubMed Scopus (2608) Google Scholar, 10Papandreou I. Cairns R.A. Fontana L. Lim A.L. Denko N.C. Cell Metab. 2006; 3: 187-197Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar). data this and it by the HIF-1α binding in PDK1 of PDK1 by hypoxia-induced to that in PDK3 knockdown cells. knockdown of PDK1 and PDK3 cell under hypoxia. of and cell were in knockdown cells with or knockdown cells, suggesting the function of The also the importance of of of the gene to a of biological The importance of PDK3 in or was in the due to a that PDK3 is expressed in and by R. Bowker-Kinley M.M. Kedishvili N.Y. Zhao Y. Popov K.M. J. Biol. Chem. 1995; 270: 28989-28994Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). However, we that PDK3 is expressed in cell and we demonstrated that hypoxia induced PDK3 in several and cancer cells suggesting it is a than a unique phenomenon of The of of PDK3 by hypoxia is the kinase activity and binding affinity of PDK3 are the highest among PDKs (7Bowker-Kinley M.M. Davis W.I. Wu P. Harris R.A. Popov K.M. Biochem. J. 1998; 329: 191-196Crossref PubMed Scopus (447) Google Scholar, A. Boulatnikov I. Popov K.M. Biochem. J. 2002; 366: 129-136Crossref PubMed Google Scholar). of PDK3 by hypoxia the of pyruvate to and PDK3 as a to of PDH it is known that high concentration of pyruvate inhibits the activity of PDK1, -2, and -4, but not PDK3 (7Bowker-Kinley M.M. Davis W.I. Wu P. Harris R.A. Popov K.M. Biochem. J. 1998; 329: 191-196Crossref PubMed Scopus (447) Google Scholar, 15Baker J.C. Yan X. Peng T. Kasten S. Roche T.E. J. Biol. Chem. 2000; 275: 15773-15781Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). In cancer cells, of PDH by of PDKs in the accumulation of pyruvate, and the pyruvate the enzymatic of PDK1, -2, and -4, but not Therefore, of PDK3 the of mitochondrial respiration. This is important in cancer cells pyruvate was also of PDK1 and PDK3 by which is elevated in cancer cells due to hypoxia or may provide a for the phenomenon of Warburg In by and molecular biological we have demonstrated that hypoxia PDK1 and PDK3 expression in cancer cells. of PDK1 and PDK3 under hypoxia metabolic switch and Given its unique feature in enzyme and biological PDK3 may the critical that the metabolic switch and in cancer cells, with elevated HIF-1α provide novel processes of cancer cells and that PDK3 may be a new and target for tumor therapy. The at the for in of HIF binding with