1331 PHENFORMIN INDUCES METABOLIC SHIFT OF PROSTATE CANCER CELLS TOWARDS UTILIZATION OF FATTY ACID METABOLISM

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research (VI)1 Apr 20131331 PHENFORMIN INDUCES METABOLIC SHIFT OF PROSTATE CANCER CELLS TOWARDS UTILIZATION OF FATTY ACID METABOLISM M. Minhaj Siddiqui, Hong Truong, Carole Sourbier, Jane B. Trepel, Peter Pinto, Len Neckers, and W. Marston Linehan M. Minhaj SiddiquiM. Minhaj Siddiqui Bethesda, MD More articles by this author , Hong TruongHong Truong Bethesda, MD More articles by this author , Carole SourbierCarole Sourbier Bethesda, MD More articles by this author , Jane B. TrepelJane B. Trepel Bethesda, MD More articles by this author , Peter PintoPeter Pinto Bethesda, MD More articles by this author , Len NeckersLen Neckers Bethesda, MD More articles by this author , and W. Marston LinehanW. Marston Linehan Bethesda, MD More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2685AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Biguanide drugs (most notably metformin) have generated significant interest lately due to their unanticipated anticancer properties. The mechanism(s) responsible for this activity remain unclear although preliminary data point to involvement of energy production pathways, either through complex 1 in the mitochondria or AMPK. We sought to further characterize the metabolic changes incurred in prostate cancer cells upon exposure to phenformin, a more potent analogue of metformin. METHODS LNCaP cells were utilized for this study. Phenformin exposures were for 2-24 hours at concentrations ranging from 0.1 to 100 uM. Western blot analysis was used to assess for changes in protein expression. The Seahorse XF96 analyzer was used to measure oxygen consumption rate (OCR) following injection of Palmitic acid bound to BSA to measure fatty acid oxidation (FAO). Cells were also exposed to 5 uM AICAR (a direct AMPK activator) and 10 uM compound C (an AMPK inhibitor) to assess the influence of AMPK on phenformin induced changes. RESULTS LNCaP cells exposed to 100 uM phenformin demonstrated a 210 % increase in OCR in response to fatty acid injection compared to LNCaP cells not exposed to phenformin (p<0.0001, Fig 1). No changes in FAO were observed after treatment of LNCaP cells with the direct AMPK activator AICAR or with the AMPK inhibitor compound C, suggesting that phenformin effect is at least not solely due to AMPK activation. Co-treatment with AICAR and phenformin demonstrated no significant change in FAO compared to phenformin alone, however co-treatment with phenformin and compound C demonstrated a statistically significant blunting of the effect of phenformin (50%; p<0.0001). Western blot analysis and densitometry demonstrated a significant induction of fatty acid synthetase and acetyl-CoA carboxylase (ACC) in phenformin-treated cells (p<0.001). CONCLUSIONS Phenformin seems to shift the metabolic balance of LNCaP cells towards oxidation of fatty acids in mitochondria. Although not directly induced by AMPK, this phenomenon seems to be modulated by AMPK activity state. Future studies will expand this study to include additional prostate cancer cell lines, and we will investigate whether targeting fatty acid metabolism represents a novel therapeutic strategy to treat prostate cancer. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e543-e544 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information M. Minhaj Siddiqui Bethesda, MD More articles by this author Hong Truong Bethesda, MD More articles by this author Carole Sourbier Bethesda, MD More articles by this author Jane B. Trepel Bethesda, MD More articles by this author Peter Pinto Bethesda, MD More articles by this author Len Neckers Bethesda, MD More articles by this author W. Marston Linehan Bethesda, MD More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...