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dc.contributor.authorAmorim, Ricardopor
dc.contributor.authorPinheiro, Célinepor
dc.contributor.authorGonçalves, Vera Mónica Mirandapor
dc.contributor.authorPereira, Helenapor
dc.contributor.authorMoyer, Mary P.por
dc.contributor.authorPreto, Anapor
dc.contributor.authorBaltazar, Fátimapor
dc.description.abstractCancer cells rely mostly on glycolysis to meet their energetic demands, producing large amounts of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). The role of MCTs in the survival of colorectal cancer (CRC) cells is scarce and poorly understood. In this study, we aimed to better understand this issue and exploit these transporters as novel therapeutic targets alone or in combination with the CRC classical chemotherapeutic drug 5-Fluorouracil. For that purpose, we characterized the effects of MCT activity inhibition in normal and CRC derived cell lines and assessed the effect of MCT inhibition in combination with 5-FU. Here, we demonstrated that MCT inhibition using CHC (a-cyano-4-hydroxycinnamic acid), DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) and quercetin decreased cell viability, disrupted the glycolytic phenotype, inhibited proliferation and enhanced cell death in CRC cells. These results were confirmed by specific inhibition of MCT1/4 by RNA interference. Notably, we showed that 5-FU cytotoxicity was potentiated by lactate transport inhibition in CRC cells, either by activity inhibition or expression silencing. These findings provide novel evidence for the pivotal role of MCTs in CRC maintenance and survival, as well as for the use of these transporters as potential new therapeutic targets in combination with CRC conventional therapy.por
dc.description.sponsorshipRicardo Amorim was recipient of the fellowships SFRH/BI/51118/ 2010 and SFRH/BD/98002/2013, from Fundação para a Ciência e Tecnologia (FCT, Portugal). This study was supported by the FCT grant ref. PTDC/SAU-FCF/104347/2008, under the scope of “Programa Operacional Temático Factores de Competitividade” (COMPETE) of “Quadro Comunitário de Apoio III” and co-financed by Fundo Comunitário Europeu FEDER. This work was also supported by FEDER through POFC – COMPETE and by FCT through project PEst-OE/BIA/UI4050/2014 and Helena Pereira’s fellowship (SFRH/BD/73139/2010).por
dc.subjectColorectal cancerpor
dc.subjectMonocarboxylate transporterspor
dc.subjectLactate transportpor
dc.subjectGlycolytic metabolismpor
dc.titleMonocarboxylate transport inhibition potentiates the cytotoxic effect of 5-fluorouracil in colorectal cancer cellspor
degois.publication.titleCancer letterspor
dc.subject.wosScience & Technologypor
sdum.journalCancer letterspor
Appears in Collections:DBio - Artigos/Papers
ICVS - Artigos em Revistas Internacionais com Referee

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