Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets

被引:199
|
作者
Miranda-Goncalves, Vera [1 ,2 ]
Honavar, Mrinalini [3 ]
Pinheiro, Celine [1 ,2 ,4 ]
Martinho, Olga [1 ,2 ]
Pires, Manuel M.
Pinheiro, Celia
Cordeiro, Michelle [5 ]
Bebiano, Gil [5 ]
Costa, Paulo [6 ]
Palmeirim, Isabel [7 ,8 ]
Reis, Rui M. [1 ,2 ,9 ]
Baltazar, Fatima [1 ,2 ]
机构
[1] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, P-4710057 Braga, Portugal
[2] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal
[3] Hosp Pedro Hispano, Dept Pathol, Matosinhos, Portugal
[4] Ctr Hosp Porto, Dept Neurosurg, Oporto, Portugal
[5] Hosp Dr Nelio Mendonca, Madeira, Portugal
[6] Ctr Hosp Montijo, Radiotherapy Serv, Barreiro, Setubal, Portugal
[7] Univ Algarve, Regenerat Med Program, Dept Ciencias Biomed & Med, Faro, Portugal
[8] Univ Algarve, Ctr Biomed Mol & Estrutural, IBB Inst Biotechnol & Bioengn, Faro, Portugal
[9] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil
关键词
CD147; CHC; glioblastomas; gliomas; glycolytic metabolism; lactate; monocarboxylate transporters; MALIGNANT GLIOMA; LACTATE TRANSPORT; LUNG-CANCER; TUMOR-CELLS; INHIBITION; CD147; TEMOZOLOMIDE; METABOLISM; GLYCOLYSIS; GROWTH;
D O I
10.1093/neuonc/nos298
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background. Gliomas exhibit high glycolytic rates, and monocarboxylate transporters (MCTs) play a major role in the maintenance of the glycolytic metabolism through the proton-linked transmembrane transport of lactate. However, their role in gliomas is poorly studied. Thus, we aimed to characterize the expression of MCT1, MCT4, and their chaperone CD 147 and to assess the therapeutic impact of MCT inhibition in gliomas. Methods. MCTs and CD 147 expressions were characterized by immunohistochemistry in nonneoplastic brain and glioma samples. The effect of CHC (MCT inhibitor) and MCT1 silencing was assessed in in vitro and in vivo glioblastoma models. Results. MCT1, MCT4, and CD 147 were overexpressed in the plasma membrane of glioblastomas, compared with diffuse astrocytomas and nonneoplastic brain. CHC decreased glycolytic metabolism, migration, and invasion and induced cell death in U251 cells (more glycolytic) but only affected proliferation in SW1088 (more oxidative). The effectiveness of CHC in glioma cells appears to be dependent on MCT membrane expression. MCT1 downregulation showed similar effects on different glioma cells, supporting CHC as an MCT1 inhibitor. There was a synergistic effect when combining CHC with temozolomide treatment in U251 cells. In the CAM in vivo model, CHC decreased the size of tumors and the number of blood vessels formed. Conclusions. This is the most comprehensive study reporting the expression of MCTs and CD 147 in gliomas. The MCT1 inhibitor CHC exhibited anti-tumoral and anti-angiogenic activity in gliomas and, of importance, enhanced the effect of temozolomide. Thus, our results suggest that development of therapeutic approaches targeting MCT1 may be a promising strategy in glioblastoma treatment.
引用
收藏
页码:172 / 188
页数:17
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