MP61-03 EVALUATION OF LACTATE TRANSPORTERS AS POTENTIAL THERAPEUTIC TARGET IN UROTHELIAL CARCINOMA
2016-03-28

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2016MP61-03 EVALUATION OF LACTATE TRANSPORTERS AS POTENTIAL THERAPEUTIC TARGET IN UROTHELIAL CARCINOMA Tilman Todenhöfer, Roland Seiler, Craig Stewart, Igor Moskalev, Jian Gao, Alireza Kamyabi, Nader Al Nakouzi, Tetsuharo Hayashi, Stephen Choi, Yuzhou Wang, Mads Daugaard, Sebastian Frees, Htoo Zarni Oo, Jörg Hennenlotter, Jens Bedke, Ladan Fazli, Arnulf Stenzl, and Peter Black Tilman TodenhöferTilman Todenhöfer More articles by this author , Roland SeilerRoland Seiler More articles by this author , Craig StewartCraig Stewart More articles by this author , Igor MoskalevIgor Moskalev More articles by this author , Jian GaoJian Gao More articles by this author , Alireza KamyabiAlireza Kamyabi More articles by this author , Nader Al NakouziNader Al Nakouzi More articles by this author , Tetsuharo HayashiTetsuharo Hayashi More articles by this author , Stephen ChoiStephen Choi More articles by this author , Yuzhou WangYuzhou Wang More articles by this author , Mads DaugaardMads Daugaard More articles by this author , Sebastian FreesSebastian Frees More articles by this author , Htoo Zarni OoHtoo Zarni Oo More articles by this author , Jörg HennenlotterJörg Hennenlotter More articles by this author , Jens BedkeJens Bedke More articles by this author , Ladan FazliLadan Fazli More articles by this author , Arnulf StenzlArnulf Stenzl More articles by this author , and Peter BlackPeter Black More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.877AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cancer cells generate a significant proportion of ATP by glycolysis, even in the presence of oxygen (Warburg effect). Lactate transporters are of utmost importance for regulation of metabolism. Recently, the significance of lactate transporters has been recognized in various cancer types, but their role in urothelial carcinoma (UC) remains mostly unknown. The aim of the present study was to investigate the functional importance of the lactate transporters MCT1 and MCT4 and their chaperone CD147 (Basigin) in preclinical models of UC. METHODS MCT1, MCT4 and CD147 protein expression was assessed in 12 UC cell lines, and in benign and malignant tissue from 180 patients with muscle invasive UC of the bladder. MCT1, MCT4 and CD147 expression were correlated with molecular subtypes in The Cancer Genome Atlas (TCGA) dataset and validated using gene expression microarray data from an independent cohort of 65 patients with muscle invasive UC. Transient silencing of MCT1, MCT4 and CD147 was performed using small-interfering RNAs (siRNAs) in three UC cell lines. Cell viability in varying concentrations of oxygen and glucose was assessed using MTS assay. We measured apoptosis and production of reactive oxygen species by flow cytometry. Moreover, intra-and extracellular lactate, extracellular acidification and the oxygen-consumption rate were determined. In vivo effects of MCT4 silencing were assessed in an orthotopic xenograft model. RESULTS Protein expression of MCT1, MCT4 and CD147 was significantly increased in cancer tissue. A high expression of MCT1, MCT4 and CD147 was associated with poor disease-specific survival after radical cystectomy. Analysis of the TCGA data as well as our own cohort of 65 UC revealed a significantly higher expression of MCT1 and MCT4 in the basal subtype. In vitro silencing of MCT4 led to a significant reduction in cell growth, a significant induction of apoptosis and an increased synthesis of reactive oxygen species. Moreover, silencing of MCT4 resulted in intracellular accumulation of lactate and reduced extracellular acidification. In vivo, stable knockdown of MCT4 significantly reduced tumor growth. CONCLUSIONS The expression of lactate transporters in UC is associated with features of aggressive tumor biology and portends a poor prognosis. Inhibition of MCT4 induces intracellular accumulation of lactate and results in decreased tumor growth in vitro and in vivo. Targeting lactate metabolism via MCT4 therefore provides a promising therapeutic approach for invasive UC. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e804 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Tilman Todenhöfer More articles by this author Roland Seiler More articles by this author Craig Stewart More articles by this author Igor Moskalev More articles by this author Jian Gao More articles by this author Alireza Kamyabi More articles by this author Nader Al Nakouzi More articles by this author Tetsuharo Hayashi More articles by this author Stephen Choi More articles by this author Yuzhou Wang More articles by this author Mads Daugaard More articles by this author Sebastian Frees More articles by this author Htoo Zarni Oo More articles by this author Jörg Hennenlotter More articles by this author Jens Bedke More articles by this author Ladan Fazli More articles by this author Arnulf Stenzl More articles by this author Peter Black More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...