The Monocarboxylate Transporters MCT1 and MCT4 Are Highly Expressed in Glioblastoma and Crucially Implicated in the Pathobiology.

Abstract

Monocarboxylate transporters (MCTs) are crucially implicated in cancer cell metabolism by transporting lactate/H+ ions and thus regulating the pH of the microenvironment. We assessed MCT1 and MCT4 expression in 98 cases of adult-type hemispheric Glioblastomas (GBMs) (IDH wild-type), along with 51 cases of IDH-mutant astrocytic and oligodendroglial tumors (grade 2-4) for comparison. U87MG and LN229 cell lines were used for in vitro analysis. Both MCT-1 and MCT-4 showed significantly higher expression in GBMs on immunohistochemistry than in IDH-mutated gliomas, which mostly showed weak or negative immunoreactivity. The mRNA expression was also in a similar line. Interestingly, in all areas of the pathological endothelial proliferation of grade 4 tumors, there was MCT-1 loss of expression, unlike the nonproliferating endothelium. High MCT1/4 expression was associated with shorter overall survival in all gliomas together but not in GBM separately. Syrosingopine, a dual MCT1/4 inhibitor, showed significant antitumor effects in both the glioma cell lines, including dose-dependent cytotoxicity, increased apoptosis, and decreased migration/invasion. The results indicated the role of MCT1/4 in the pathobiology of GBM and the diagnostic utility at the immunohistochemical level. Syrosingopine, an antihypertensive agent with good CNS penetration and previously used in different malignancies, may be an essential therapeutic adjunct in GBM.