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Selective inhibition of the lactate transporter MCT4 reduces growth of invasive bladder cancer

Tilman Todenhöfer, Roland Seiler, Craig Stewart, Igor Moskalev, Jian Gao, Simroop Ladhar, Alireza Kamyabi, Nader Al Nakouzi, Tetsutaro Hayashi, Stephen Choi, Yuzhuo Wang, Sebastian Frees, Mads Daugaard, Htoo Zarni Oo, Pascale Fisel, Matthias Schwab, Elke Schaeffeler, James Douglas, Jörg Hennenlotter, Jens Bedke, Ewan A Gibb, Ladan Fazli, Arnulf Stenzl, Peter C Black
Molecular Cancer Therapeutics2018
Introduction & Objectives: 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 monocarboxylate transporter (MCT) 4 in preclinical models of UC and to assess its relevance in patient tumors. Materials & Methods: The association of MCT4 expression with molecular subtypes and outcome was determined in The Cancer Genome Atlas (TCGA) cohort and two independent cohorts of patients with UC. Silencing of MCT4 was performed using small-interfering RNAs in UC cell lines. Effects of MCT4 inhibition on cell growth, apoptosis and production of reactive oxygen species were assessed. Moreover, effects on lactate efflux were determined. The in vivo effects of MCT4 silencing were assessed in an orthotopic xenograft model. Results: MCT4 expression was higher in the basal subtype. Decreased MCT4 methylation, and increased RNA and protein expression were associated with worse overall survival. Inhibition of MCT4 led to a reduction in cell growth, induction of apoptosis and an increased synthesis of reactive oxygen species. MCT4 inhibition resulted in intracellular accumulation of lactate. In vivo, stable knockdown of MCT4 reduced tumor growth. Conclusions: The expression of MCT4 in UC is associated with features of aggressive tumor biology and portends a poor prognosis. Inhibition of MCT4 results in decreased tumor growth in vitro and in vivo. Targeting lactate metabolism via MCT4 therefore provides a promising therapeutic approach for invasive UC, especially in the basal subtype.

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