World Journal of Urology

, Volume 31, Issue 5, pp 1191–1196 | Cite as

Expression parameters of the metabolic pathway genes pyruvate dehydrogenase kinase-1 (PDK-1) and DJ-1/PARK7 in renal cell carcinoma (RCC)

  • Daniel Baumunk
  • Uta Reichelt
  • Jannis Hildebrandt
  • Hans Krause
  • Jan Ebbing
  • Hannes Cash
  • Kurt Miller
  • Martin Schostak
  • Steffen Weikert
Original Article



Metabolic adaptations, such as increases in glucose and energy metabolism, play a pivotal role in the biology of RCC. PDK-1 and DJ-1/PARK7 are thought to control metabolic pathways in cancer. We investigated the expression of PDK-1 and DJ-1/PARK7 in RCC and their prognostic relevance.


RCC tumor tissue and corresponding normal parenchyma samples were obtained from 91 patients with clear cell RCC. Expression of PDK-1 and DJ-1/PARK7 was determined on the mRNA and protein levels using quantitative RT-PCR and immunohistochemistry. Expression ratios tumor/normal were analyzed for associations with pathological stage and grade (Kruskal–Wallis ANOVA, chi-square test). Potential associations with progression-free and overall survival were analyzed using Cox regression models.


PDK-1 mRNA expression was up-regulated as compared to normal tissue (p < 0.001). Differences were observed by tumor stage (p < 0.05) with a trend toward lower expression with increasing stage (p > 0.01). Expression ratio tumor/normal also showed differences by tumor stage with the lowest ratio observed in advanced (pT3) disease. MRNA expression data were confirmed on the protein level with the lowest protein expression in pT3 tumors. PDK-1 expression ratio tumor/normal was inversely associated with outcome after adjustment for stage and grade (HR, 0.54; 95 % CI, 0.31–0.94). No associations observed for DJ-1/PARK7 expression.


PDK is up-regulated in RCC, but down-regulation may be associated with progression toward a metastasizing behavior. Given the role of PDK-1 in the control of glucose metabolism, aerobic glycolysis via up-regulation of PDK-1 may be an early event in RCC development, but less relevant for the progression toward an aggressive phenotype.


PDK-1 DJ-1/PARK7 Renal cell carcinoma Glucose metabolism 


  1. 1.
    Catchpole G, Platzer A, Weikert C, Kempkensteffen C, Johannsen M, Krause H, Jung K, Miller K, Willmitzer L, Selbig J, Weikert S (2011) Metabolic profiling reveals key metabolic features of renal cell carcinoma. J Cell Mol Med 15(1):109–118. doi:10.1111/j.1582-4934.2009.00939.x PubMedCrossRefGoogle Scholar
  2. 2.
    Garber K (2006) Energy deregulation: licensing tumors to grow. Science 312(5777):1158–1159. doi:10.1126/science.312.5777.1158 PubMedCrossRefGoogle Scholar
  3. 3.
    McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A (2008) Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 283(33):22700–22708. doi:10.1074/jbc.M801765200 PubMedCrossRefGoogle Scholar
  4. 4.
    Korotchkina LG, Patel MS (2001) Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. J Biol Chem 276(40):37223–37229. doi:10.1074/jbc.M103069200 PubMedCrossRefGoogle Scholar
  5. 5.
    Dang CV (2007) The interplay between MYC and HIF in the Warburg effect. Ernst Schering Found Symp Proc 4:35–53PubMedGoogle Scholar
  6. 6.
    Kim JW, Gao P, Liu YC, Semenza GL, Dang CV (2007) Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol 27(21):7381–7393. doi:10.1128/MCB.00440-07 PubMedCrossRefGoogle Scholar
  7. 7.
    Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3(3):187–197. doi:10.1016/j.cmet.2006.01.012 PubMedCrossRefGoogle Scholar
  8. 8.
    Marcondes AM, Li X, Gooley TA, Milless B, Deeg HJ (2010) Identification of DJ-1/PARK-7 as a determinant of stroma-dependent and TNF-alpha-induced apoptosis in MDS using mass spectrometry and phosphopeptide analysis. Blood 115(10):1993–2002. doi:10.1182/blood-2009-08-236992 PubMedCrossRefGoogle Scholar
  9. 9.
    Vasseur S, Afzal S, Tardivel-Lacombe J, Park DS, Iovanna JL, Mak TW (2009) DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses. Proc Natl Acad Sci USA 106(4):1111–1116. doi:10.1073/pnas.0812745106 PubMedCrossRefGoogle Scholar
  10. 10.
    Sitaram RT, Cairney CJ, Grabowski P, Keith WN, Hallberg B, Ljungberg B, Roos G (2009) The PTEN regulator DJ-1 is associated with hTERT expression in clear cell renal cell carcinoma. Int J Cancer 125(4):783–790. doi:10.1002/ijc.24335 PubMedCrossRefGoogle Scholar
  11. 11.
    Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847PubMedCrossRefGoogle Scholar
  12. 12.
    Schraml P, Kononen J, Bubendorf L, Moch H, Bissig H, Nocito A, Mihatsch MJ, Kallioniemi OP, Sauter G (1999) Tissue microarrays for gene amplification surveys in many different tumor types. Clin Cancer Res 5(8):1966–1975PubMedGoogle Scholar
  13. 13.
    Mirlacher M, Kasper M, Storz M, Knecht Y, Durmuller U, Simon R, Mihatsch MJ, Sauter G (2004) Influence of slide aging on results of translational research studies using immunohistochemistry. Mod Pathol 17(11):1414–1420. doi:10.1038/modpathol.3800208 PubMedCrossRefGoogle Scholar
  14. 14.
    Jung M, Ramankulov A, Roigas J, Johannsen M, Ringsdorf M, Kristiansen G, Jung K (2007) In search of suitable reference genes for gene expression studies of human renal cell carcinoma by real-time PCR. BMC Mol Biol 8:47. doi:10.1186/1471-2199-8-47 PubMedCrossRefGoogle Scholar
  15. 15.
    Merino MJ, Valera VA (2011) Misdiagnosis of clear cell renal cell carcinoma. Nat Rev Urol 8(6):321–333. doi:10.1038/nrurol.2011.64 PubMedCrossRefGoogle Scholar
  16. 16.
    Wigfield SM, Winter SC, Giatromanolaki A, Taylor J, Koukourakis ML, Harris AL (2008) PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer. Br J Cancer 98(12):1975–1984. doi:10.1038/sj.bjc.6604356 PubMedCrossRefGoogle Scholar
  17. 17.
    Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL (2005) Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. Neoplasia 7(1):1–6PubMedCrossRefGoogle Scholar
  18. 18.
    Koukourakis MI, Giatromanolaki A, Bougioukas G, Sivridis E (2007) Lung cancer: a comparative study of metabolism related protein expression in cancer cells and tumor associated stroma. Cancer Biol Ther 6(9):1476–1479PubMedCrossRefGoogle Scholar
  19. 19.
    Pan JG, Mak TW (2007) Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE 2007(381):pe14. doi:10.1126/stke.3812007pe14 PubMedGoogle Scholar
  20. 20.
    Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99(7):989–994. doi:10.1038/sj.bjc.6604554 PubMedCrossRefGoogle Scholar
  21. 21.
    Cairns RA, Papandreou I, Sutphin PD, Denko NC (2007) Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Proc Natl Acad Sci USA 104(22):9445–9450. doi:10.1073/pnas.0611662104 PubMedCrossRefGoogle Scholar
  22. 22.
    Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11(1):37–51. doi:10.1016/j.ccr.2006.10.020 PubMedCrossRefGoogle Scholar
  23. 23.
    Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120(1):253–260. doi:10.1007/s10549-009-0435-9 PubMedCrossRefGoogle Scholar
  24. 24.
    Pathania D, Millard M, Neamati N (2009) Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv Drug Deliv Rev 61(14):1250–1275. doi:10.1016/j.addr.2009.05.010 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Daniel Baumunk
    • 1
    • 4
  • Uta Reichelt
    • 3
  • Jannis Hildebrandt
    • 2
  • Hans Krause
    • 2
  • Jan Ebbing
    • 2
  • Hannes Cash
    • 2
  • Kurt Miller
    • 2
  • Martin Schostak
    • 1
  • Steffen Weikert
    • 2
  1. 1.Department of UrologyUniversitätsklinikum Magdeburg A. ö. R.MagdeburgGermany
  2. 2.Department of UrologyCharité-Universitätsmedizin Berlin10117Berlin
  3. 3.Department of PathologyCharité-Universitätsmedizin BerlinBerlinGermany
  4. 4.Klinik für Urologie und KinderurologieUniversitätsklinikum Magdeburg A. ö. R.MagdeburgGermany

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