期刊
ONCOTARGET
卷 6, 期 22, 页码 19177-19189出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3910
关键词
monocarboxylate transporters; breast carcinoma; hypoxia; lactate; Warburg effect
资金
- Fundacao para a Ciencia e a Tecnologia (FCT) under the scope of Programa Operacional Tematico Factores de Competitividade (COMPETE) of Quadro Comunitario de Apoio III [PTDC/SAU-FCF/104347/2008]
- Fundo Europeu De Desenvolvimento Regional (FEDER)
- FCT [SFRH/BD/87139/2012, SFRH/BD/51997/2012, SFRH/BD/68270/2010, SFRH/BPD/69479/2010]
- [UMINHO/BPD/18/2014]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/87139/2012, SFRH/BD/51997/2012, SFRH/BD/68270/2010, PTDC/SAU-FCF/104347/2008] Funding Source: FCT
Background: Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as Warburg effect. Acidification of the tumour microenvironment by lactate extrusion, performed by lactate transporters (MCTs), is associated with higher cell proliferation, migration, invasion, angiogenesis and increased cell survival. Previously, we have described MCT1 up-regulation in breast carcinoma samples and demonstrated the importance of in vitro MCT inhibition. In this study, we performed siRNA knockdown of MCT1 and MCT4 in basal-like breast cancer cells in both normoxia and hypoxia conditions to validate the potential of lactate transport inhibition in breast cancer treatment. Results: The effect of MCT knockdown was evaluated on lactate efflux, proliferation, cell biomass, migration and invasion and induction of tumour xenografts in nude mice. MCT knockdown led to a decrease in in vitro tumour cell aggressiveness, with decreased lactate transport, cell proliferation, migration and invasion and, importantly, to an inhibition of in vivo tumour formation and growth. Conclusions: This work supports MCTs as promising targets in cancer therapy, demonstrates the contribution of MCTs to cancer cell aggressiveness and, more importantly, shows, for the first time, the disruption of in vivo breast tumour growth by targeting lactate transport.
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