Crosstalk between sphingosine-1-phosphate and EGFR signalling pathways enhances human glioblastoma cell invasiveness

We show that glioblastoma multiform (GBM) cells overexpressing the constitutively active form of the epidermal growth factor receptor (EGFRvIII; EGFR+ cells) possess greater invasive properties and have higher levels of extracellular sphingosine-1-phosphate (S1P) and increased sphingosine kinase-1 (SK1) activity than the empty vector-expressing cells. Notably, the inhibition of SK1 or S1P receptors decreases the invasiveness of EGFR+ cells. Moreover, EGFR and MEK1 inhibitors reduce both SK1 activation and cell invasion suggesting that the enhanced invasiveness observed in the EGFR+ cells depends on the increased S1P secretion, downstream of the EGFRvIII-ERK-SK1-S1P pathway. Altogether, our study indicates that in glioblastoma multiform cells, EGFRvIII is connected with the S1P signaling pathway to enhance cell invasiveness and tumor progression.