MP35-14 THE CONTRIBUTION OF METABOLIC REMODELING TO THERAPY RESISTANCE IN RENAL CANCER

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2014MP35-14 THE CONTRIBUTION OF METABOLIC REMODELING TO THERAPY RESISTANCE IN RENAL CANCER Sunil Sudarshan, Dustin Gayheart, Tanner Hughes, Akash Kapadia, and Dan Benson Sunil SudarshanSunil Sudarshan More articles by this author , Dustin GayheartDustin Gayheart More articles by this author , Tanner HughesTanner Hughes More articles by this author , Akash KapadiaAkash Kapadia More articles by this author , and Dan BensonDan Benson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1057AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Therapy resistance is a significant obstacle in the treatment of patients with advanced renal cell carcinoma (RCC). One of the proposed mechanisms underlying therapy resistance is the propensity of RCC to utilize glycolysis in lieu of the tricarboxylic acid (TCA) cycle/oxidative phosphorylation for rapid energy production, a phenomenon known as the Warburg effect. In this study, we interrogated the biologic basis of the Warburg effect in RCC as well as its contribution to therapy resistance. METHODS Comparative gene expression analysis by mRNA microarray demonstrates a marked increase in the expression of Pyruvate Dehydrogenase Kinase-1 (PDK-1) in metastatic RCC compared with both normal tissue and primary RCC. PDK-1 promotes glycolytic metabolism by blocking the entry of pyruvate into the TCA cycle thereby inhibiting oxidative phosphorylation. Based on these data, we investigated the contribution of PDK-1 overexpression to therapy resistance utilizing two pharmacologic inhibitors of PDK-1, dichloroacetate (DCA) and phenylbutyrate (PB). RCC cell lines A498 and 786-O were exposed to Sorafenib only and PDK-1 inhibitors (DCA or PB) alone in order to determine the drug-response relationship. Minimally inhibitory doses of PDK-1 inhibitors were then used in combination with increasing doses of Sorafenib. MTS assays were performed in each experimental design in order to determine cell proliferation and viability. In tandem, Annexin V staining was utilized to determine the contribution of apoptosis to cell death following treatments. RESULTS PDK-1 inhibition with either DCA or PB sensitized 786-O RCC cells to the cytotoxic effect of sorafenib. These data reached statistical significance (p<0.05). Similarly, PB sensitized A498 cells to sorafenib (p<0.05). Furthermore, the differences in cell viability between control groups (no treatment) and PDK-1 inhibitor (DCA or PB) alone were not statistically significant. Annexin V staining revealed significantly increased apoptosis with sorafenib/PB cotreatment when compared to Sorafenib alone. CONCLUSIONS Activation of the TCA cycle via inhibition of PDK-1 potentiates the anti-tumor activity of Sorafenib. Although further characterization of the role of PDK-1 inhibitors in tumor growth suppression is required, our preliminary data suggests an important role of the Warburg effect demonstrated by RCC in the development of treatment resistance. Furthermore, unlocking metabolic pathways associated with this phenomenon may be the key to a novel therapeutic approach in the treatment of RCC. Rising Star Award-Urology Care Foundation © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e375-e376 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Sunil Sudarshan More articles by this author Dustin Gayheart More articles by this author Tanner Hughes More articles by this author Akash Kapadia More articles by this author Dan Benson More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...