Selective Inhibition of the Lactate Transporter MCT4 Reduces Growth of Invasive Bladder Cancer
| Autor: | Yuzhuo Wang, Stephen Yiu Chuen Choi, Elke Schaeffeler, James Douglas, Jian Gao, Ladan Fazli, Craig Stewart, Ewan A. Gibb, Jörg Hennenlotter, Igor Moskalev, T. Hayashi, Arnulf Stenzl, Sebastian Frees, Pascale Fisel, Roland Seiler, Mads Daugaard, Htoo Zarni Oo, Jens Bedke, Peter C. Black, Nader Al Nakouzi, Tilman Todenhöfer, Matthias Schwab, Simroop Ladhar, Alireza Kamjabi |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Monocarboxylic Acid Transporters 0301 basic medicine Cancer Research Small interfering RNA Invasive urothelial carcinoma Mice Nude Muscle Proteins Apoptosis Models Biological 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans Gene silencing Lactic Acid Cell Proliferation Monocarboxylate transporter Gene knockdown Bladder cancer biology Cell growth DNA Methylation medicine.disease Survival Analysis Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic 030104 developmental biology Urinary Bladder Neoplasms Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Reactive Oxygen Species |
| Zdroj: | Molecular Cancer Therapeutics. 17:2746-2755 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-18-0107 |
| Popis: | The significance of lactate transporters has been recognized in various cancer types, but their role in urothelial carcinoma remains mostly unknown. The aim of this study was to investigate the functional importance of the monocarboxylate transporter (MCT) 4 in preclinical models of urothelial carcinoma and to assess its relevance in patient tumors. 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 urothelial carcinoma. Silencing of MCT4 was performed using siRNAs in urothelial carcinoma cell lines. Effects of MCT4 inhibition on cell growth, apoptosis, and production of reactive oxygen species (ROS) were assessed. Moreover, effects on lactate efflux were determined. The in vivo effects of MCT4 silencing were assessed in an orthotopic xenograft model. MCT4 expression was higher in the basal subtype. Decreased MCT4 methylation and increased RNA and protein expression were associated with worse overall survival (OS). Inhibition of MCT4 led to a reduction in cell growth, induction of apoptosis, and an increased synthesis of ROS. MCT4 inhibition resulted in intracellular accumulation of lactate. In vivo, stable knockdown of MCT4 reduced tumor growth. The expression of MCT4 in urothelial carcinoma 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 urothelial carcinoma, especially in the basal subtype. |
| Databáze: | OpenAIRE |
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