Previous studies have shown that neurokinin 1 receptor (NK1R) occurs naturally in human glioblastomas and its stimulation causes cell proliferation. In the present study we show that stimulation of NK1R in human U373 glioblastoma cells by substance P increases Akt phosphorylation by 2.5‐fold, with an EC50 of 57 nM. Blockade of NK1R lowers basal phosphorylation of Akt, indicating the presence of a constitutively active form of NK1R; similar results are seen in U251 MG and DBTRG‐05 glioblastoma cells. Linkage of NK1R to Akt implicates NK1R in apoptosis of glioblastoma cells. Indeed, treatment of serum‐starved U373 cells with substance P reduces apoptosis by 53 ± 1% (p < 0.05), and treatment with NK1R antagonist L‐733,060 increases apoptosis by 64 ± 16% (p < 0.01). Further, the blockade of NK1R in human glioblastoma cells with L‐733,060 causes cleavage of Caspase‐3 and proteolysis of poly (ADP‐ribose) polymerase. Experiments designed to elucidate the mechanism of NK1R‐mediated Akt phosphorylation revealed total involvement of non‐receptor tyrosine kinase Src and phosphatidyl‐3‐kinase, a partial involvement of epidermal growth factor receptor, and no involvement of mitogen‐activated protein/extracellular signal‐related kinase. Taken together, the results of the present study indicate a key role for NK1R in glioblastoma apoptosis.

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