title: Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target.
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 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.
authors.affiliation: Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London, WC2A 3LY, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Gerlinger
authors.forename: Claudio R
authors.initials: CR
authors.lastname: Santos
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: Pierre
authors.initials: P
authors.lastname: Martinez
authors.forename: David
authors.initials: D
authors.lastname: Endesfelder
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Burrell
authors.forename: Marcus
authors.initials: M
authors.lastname: Vetter
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Saunders
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelly
authors.forename: Karl
authors.initials: K
authors.lastname: Dykema
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclercq
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Patard
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D018572:Disease-Free Survival; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D019344:Lactic Acid / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D012333:RNA, Messenger; C406962:SLC16A4 protein, human; D019344:Lactic Acid