Neurokinin-1 Receptor Directly Mediates Breast Cancer Cell Migration By Up-regulation Of Matrix Metalloproteinase-2(MMP-2)and Membrane Type 1 Matrix Metalloproteinase(MT1-MMP)

Neurokinin-1 receptor(NK1R)was naturally expressed on human breast cancer cell.Its activation mediates breast cancer cell proliferation.However,whether NK1R is directly involved in breast cancer cell migration have not been reported.In the present study,our aim was to investigate the activation of neurokinin-1 receptor mediates breast cancer cell T-47D migration and it related signal pathway.Our results indicated that human hemokinin-1(hHK-1)dose-dependently promoted the migration of T-47D cell.Moreover,NK1R antagonist L732138 dose-dependently reduced the migration of T-47D cell induced by hHK-1.In addition,our results demonstrated that T-47D cell migration induced by hHK-1 was mediated by the enhancement of MMP-2 activity and the expression of MMP-2 and MT1-MMP.The involved mechanisms were also investigated in the present study.In T-47D cell,hHK-1 could rapidly increase the phosphorylation of MAPKs and Akt;additionally,inhibition of ERK1/2,JNK and Akt effectively reduced MMP-2 expression induced by hHK-1.We further demonstrated PKA inhibitor RP-cAMP dose-dependently reduced phosphorylation of ERK1/2,but almost has no effect on the phosphorylation of JNK and Akt.PKC inhibitor Bisindolymaleimide I dose-dependently reduced phosphorylation of ERK1/2,JNK and Akt.It means that both Gq-PLA pathway and Gq-PLC pathway are involved in the migration of T-47D cell induced by NK1R activation.hHK-1 could also significantly increase the phosphorylation of NK-?B and c-Jun in T-47D cell.These effects were blocked by the pretreatments with specific inhibitors for AP-1 or NF-?B inhibitor.Moreover,inhibition of ERK1/2,JNK and Akt effectively reduced phosphorylation of NK-?B and c-Jun,which strongly blocked the MMPs up-regulation induced by hHK-1 and subsequently reduced the migration of T-47D cell.Taken together,our results suggested that NK1R is a potential regulator of human breast cancer cell migration via up-regulation of MMP-2 and MT1-MMP.