Neuropeptide Substance P Enhances Inflammation-Mediated Tumor Signaling Pathways and Migration and Proliferation of Head and Neck Cancers.

Abstract

Head and neck cancers (HNC) are extremely aggressive, highly recurrent, and the sixth most common cancer worldwide. Neuropeptide substance P, along with its primary receptor, neurokinin-1 (NK-1R), is overexpressed in HNC and is a central player in inflammation and growth and metastasis of several cancers. However, the precise SP-mediated signaling that promotes HNC progression remains ill defined. Using a panel of HNC lines, in this study, we investigated the effects of SP on proliferation and migration of HNC. Tumor cells were also treated with SP and alterations in inflammatory cytokines and chemokines, and their cognate receptors were analyzed by real-time PCR. Furthermore, we investigated the role of SP in inducing epithelial-mesenchymal transition (EMT), and matrix metalloproteases that promote tumor invasion. Our results showed that SP significantly increased tumor cell proliferation and migration and induced the expression of several genes that promote tumor growth, invasion, and metastasis which was suppressed by a specific NK1R antagonist L-703606. SP also activated NFκB that was suppressed on inhibiting NK1R. Collectively, our data shows that SP-NK1R-mediated inflammatory signaling comprises an important signaling axis in promoting HNC and may prove to be effective clinical target against HNC cells that are resistant to traditional therapy.