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

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 BRAFV600E-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). (C) 2021 Published by Elsevier Inc.

Automated summary

The study identified NHE1 as a downstream target of BRAF(V600E) and an upstream factor of ERK, with a positive feedback loop between NHE1 and ERK phosphorylation promoting GBM cell proliferation and invasion. Both NHE1 inhibitor, BRAF(V600E) inhibitor, and their combination showed efficacy in suppressing the growth and invasion abilities of GBM cells, with the combination demonstrating the best results.