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 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 . • NHE1 phosphorylation (p-NHE1) was regulated by BRAF V600E in glioblastoma (GBM) cells. • The p-NHE1 increased p-ERK level, while activated ERK also positively regulated p-NHE1. • Positive feedback-loop of p-NHE1-p-ERK contributed to GBM development. • Combination of BRAF V600E and NHE1 inhibitors showed better therapeutic effect than single drug for BRAF V600E GBM.