Please use this identifier to cite or link to this item: https://hdl.handle.net/1822/74346

TitleMCT1 is a new prognostic biomarker and its therapeutic inhibition boosts response to temozolomide in human glioblastoma
Author(s)Miranda-Gonçalves, Vera
Gonçalves, Celine Saraiva
Granja, Sara Costa
Castro, Joana Isabel Martins Cosme Vieira
Reis, Rui M.
Costa, Bruno M.
Baltazar, Fátima
KeywordsMonocarboxylate transporters
Glioblastoma
Lactate
Warburg effect
Prognostic biomarker
Issue date11-Jul-2021
PublisherMultidisciplinary Digital Publishing Institute (MDPI)
JournalCancers
CitationMiranda-Gonçalves, V.; Gonçalves, C.S.; Granja, S.; Vieira de Castro, J.; Reis, R.M.; Costa, B.M.; Baltazar, F. MCT1 Is a New Prognostic Biomarker and Its Therapeutic Inhibition Boosts Response to Temozolomide in Human Glioblastoma. Cancers 2021, 13, 3468. https://doi.org/10.3390/cancers13143468
Abstract(s)<i>Background:</i> Glioblastomas (GBMs) present remarkable metabolism reprograming, in which many cells display the “Warburg effect”, with the production of high levels of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). We described previously that MCT1 is up-regulated in human GBM samples, and MCT1 inhibition decreases glioma cell viability and aggressiveness. In the present study, we aimed to unveil the role of MCT1 in GBM prognosis and to explore it as a target for GBM therapy in vivo. <i>Methods:</i> MCT1 activity and protein expression were inhibited by AR-C155858 and CHC compounds or stable knockdown with shRNA, respectively, to assess in vitro and in vivo the effects of MCT1 inhibition and on response of GBM to temozolomide. Survival analyses on GBM patient cohorts were performed using Cox regression and Log-rank tests. <i>Results:</i> High levels of MCT1 expression were revealed to be a predictor of poor prognosis in multiple cohorts of GBM patients. Functionally, in U251 GBM cells, MCT1 stable knockdown decreased glucose consumption and lactate efflux, compromising the response to the MCT1 inhibitors CHC and AR-C155858. MCT1 knockdown significantly increased the survival of orthotopic GBM intracranial mice models when compared to their control counterparts. Furthermore, MCT1 downregulation increased the sensitivity to temozolomide in vitro and in vivo, resulting in significantly longer mice survival. <i>Conclusions:</i> This work provides first evidence for MCT1 as a new prognostic biomarker of GBM survival and further supports MCT1 targeting, alone or in combination with classical chemotherapy, for the treatment of GBM.
TypeArticle
URIhttps://hdl.handle.net/1822/74346
DOI10.3390/cancers13143468
e-ISSN2072-6694
Publisher versionhttps://www.mdpi.com/2072-6694/13/14/3468
Peer-Reviewedyes
AccessOpen access
Appears in Collections:BUM - MDPI

Files in This Item:
File Description SizeFormat 
cancers-13-03468-v3.pdf2,44 MBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons

Partilhe no FacebookPartilhe no TwitterPartilhe no DeliciousPartilhe no LinkedInPartilhe no DiggAdicionar ao Google BookmarksPartilhe no MySpacePartilhe no Orkut
Exporte no formato BibTex mendeley Exporte no formato Endnote Adicione ao seu ORCID