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

Marco Gerlinger 1, 2 Claudio Santos 2 Bradley Spencer-Dene 2 Pierre Martinez 2 David Endesfelder 2 Rebecca Burrell 2 Marcus Vetter 3 Ming Jiang 2 Rebecca E Saunders 2 Gavin Kelly 2 Nathalie Rioux-Leclercq 4 Gordon Stamp 2 Jean Jacques Patard 5 James Larkin 3 Michael Howell 2 Charles Swanton 2, 6, *
* Auteur correspondant
1 Barts Cancer Institute
2 Cancer Research UK London Research Institute
3 Department of Medical Oncology
4 Service d'anatomie et cytologie pathologiques [Rennes]
5 Service d'urologie
6 Cancer Institute
Abstract : Clear 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 over-expressed 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 8 ccRCC lines tested and was the 7th most over-expressed gene in a meta-analysis of 5 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. Intratumoral 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.
Keywords : renal cell carcinoma lactate transport MCT4 SLC16A3 cancer metabolism Warburg effect survival regulator therapeutic target
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Journal of Pathology, Wiley, 2012, 227 (2), pp.146-156. 〈10.1002/path.4006〉
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Contributeur : Hervé De Villemeur <>
Soumis le : jeudi 15 mars 2012 - 14:46:25
Dernière modification le : mercredi 16 mai 2018 - 11:23:34

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Marco Gerlinger, Claudio Santos, Bradley Spencer-Dene, Pierre Martinez, David Endesfelder, et al.. Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target.. Journal of Pathology, Wiley, 2012, 227 (2), pp.146-156. 〈10.1002/path.4006〉. 〈inserm-00679340〉

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