The positive feedback loop of NHE1-ERK phosphorylation mediated by BRAFV600E mutation contributes to tumorigenesis and development of glioblastoma

Abstract

The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation V600E (BRAF^V600E) 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 BRAF^V600E signal pathway and NHE1 in GMB cells remains unclear. This study found that NHE1 was a downstream target of BRAF^V600E 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 BRAF^V600E mutation contributing to the proliferation and invasion of GBM cells. Moreover, the proliferation and invasion abilities of BRAF^V600E-mutant and BRAF wild type GBM cells were all suppressed by the NHE1 inhibitor, BRAF^V600E 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 BRAF^V600E and NHE1 inhibitors could be considered as a new therapeutic regimen for GBM, especially for GBM with BRAF^V600E.

Keywords: BRAF(V600E) mutation; ERK; Glioblastoma; Inhibitor; NHE1.