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