Abstract
The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation V600E (BRAFV600E) is involved in glioblastoma multiforme (GBM). Na/H exchanger 1 (NHE1), a main pH regulator affecting cell microenvironment, is hyper-expressed in GBM. However, the relationship between BRAFV600E signal pathway and NHE1 in GMB cells remains unclear. This study found that NHE1 was a downstream target of BRAFV600E and an upstream factor of extracellular signal-regulated kinase (ERK). In addition, there was a positive feedback loop between NHE1-ERK phosphorylation under regulation of BRAFV600E mutation contributing to the proliferation and invasion of GBM cells. Moreover, the proliferation and invasion abilities of BRAFV600E-mutant and BRAF wild type GBM cells were all suppressed by the NHE1 inhibitor, BRAFV600E inhibitor and combination of them. The inhibitory effect of combination of the two inhibitors was better than each single drug both in vitro and in vivo. Combination of BRAFV600E and NHE1 inhibitors could be considered as a new therapeutic regimen for GBM, especially for GBM with BRAFV600E.
Highlights
Glioma accounts for about 45% of all intracranial tumors, of which more than half are glioblastoma multiforme (GBM)
The FIR value of AM38 cells, which could indirectly reflect Na/H exchanger 1 (NHE1) activity, was markedly higher than that of U251 cells (P = 0.005) (Fig. 1D). These data suggested that the expression, phosphorylation level and activity of NHE1 might be related to BRAFV600E mutation
The present study found that the expression, phosphorylation and activity of NHE1 in BRAFV600E-mutant AM38 cells were all higher than those in BRAFWT U251 cells
Summary
Glioma accounts for about 45% of all intracranial tumors, of which more than half are glioblastoma multiforme (GBM). The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) is an important transduction factor of downstream mitogen activated protein kinase (MAPK) signaling pathway[3]. The 600th amino acid residue gene of BRAF changes from valine to glutamic acid to form continuous activated BRAFV600E, which leads to the continuous activation of MAPK signaling pathway and changes of tumor cell proliferation and metabolism[3]. BRAFV600E inhibitors Vemurafenib (PLX4032) and dabrafenib (GSK21118436) have been approved for the treatment of BRAFV600E mutant melanoma[5]. Studies in gliomas have shown that the inhibition of MAPK signaling pathway by BRAFV600E inhibitor alone is not persistent, which may be due to drug resistance or activation of compensatory mechanism[6,7]. Further search for new therapeutic targets could provide new ideas for the treatment of BRAFV600E mutant GBM
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