Genome‐wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target

Journal of Pathology - Tập 227 Số 2 - Trang 146-156 - 2012
Marco Gerlinger1,2,3, Cláudio R. Santos2,3, Bradley Spencer‐Dene4, Pierre Martinez3, David Endesfelder3, Rebecca A. Burrell3, Marcus Vetter5, Ming Jiang6, Rebecca E. Saunders6, Gavin Kelly7, Karl Dykema8, Nathalie Rioux‐Leclercq9, Gordon Stamp4, Jean‐Jacques Patard10, James Larkin5, Michael Howell6, Charles Swanton3,11
1Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
2these authors contributed equally to this work
3Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London, WC2A 3LY, UK
4Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London, WC2A 3LY, UK
5Royal Marsden Hospital, Department of Medical Oncology, Renal Unit, Fulham Road London, UK
6High Throughput Screening Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London, WC2A 3LY, UK
7Bioinformatics & Biostatistics Service, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London, WC2A 3LY, UK
8Lab of Computational Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA
9Department of Pathology, Rennes University Hospital, Rennes, France
10Department of Urology, Bicêtre Hospital, Paris XI University, Paris, France
11University College London Cancer Institute, Huntley Street, London, UK

Tóm tắt

AbstractClear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome‐wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently overexpressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all eight ccRCC lines tested and was the seventh most overexpressed gene in a meta‐analysis of five ccRCC expression datasets. MCT4 silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intra‐tumoural heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse‐free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Journal of Pathology

Tập 227 Số 2

146-156

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