| Neurokinin-1 receptor (NKIR) occurs naturally on human glioblastomas. Its activation mediates glioma cell proliferation. However, it is unknown whether NKIR is directly involved in tumor cell migration. In present study, we found human hemokinin-1 (hHK-1), via NKIR, dose-dependently promoted the migration of U-251 and U-87 cell. In addition, we showed that hHK-1 enhanced the activity of MMP-2 and the expression of MMP-2 and MT1-MMP which were responsible for the cell migration, because neutralizing the MMPs with antibodies decreased the cell migration. The involved mechanisms were then investigated. In U-251, hHK-1 induced significant calcium efflux; PLC inhibitor U-73122 reduced the calcium mobilization, the up-regulation of MMP-2 and MTl-MMP and the cell migration induced by hHK-1, which meant the migration effect of NKIR was mainly mediated through Gq-PLC pathway. We further demonstrated hHK-lboosted rapid phosphorylation of ERK, JNK and Akt; inhibition of ERK and Akt effectively reduced MMP-2 induction by hHK-1; meanwhile inhibition of ERK, JNK and Akt reduced the MTl-MMP induction. hHK-1 stimulated significant phosphorylation of p65 and c-JUN in U-251. Reporter gene assays indicated hHK-1 enhanced both AP-1 and NF-kB activity; inhibition of ERK, JNK and Akt dose-dependently suppressed the NF-kB activity; only the inhibition of ERK significantly suppressed the AP-1 activity. Treatment with specific inhibitors for AP-1 or NF-kB strongly blocked the MMPs up-regulation by hHK-1. Taken together, our data suggested NKIR was a potential regulator of human glioma cell migration by the up-regulation of MMP-2 and MTl-MMP. |
