EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor...

In squamous cell carcinoma, the levels of nitric oxide (NO) derived from inducible NO synthase (iNOS) and prostaglandin E2 (PGE2) derived from cyclooxygenase-2 (COX-2) originated from tumor cells or tumor-associated inflammatory cells have been reported to correlate with tumor growth, metastasis, and angiogenesis. The present study examined the role of the iNOS signaling pathway in PGE2-mediated tumor invasiveness and proliferation in squamous cell carcinoma, A431, and SCC-9 cells. Cell invasion and proliferation promoted by PGE2 were blocked by iNOS silencing RNA or iNOS/guanylate cyclase (GC) pharmacological inhibition. Consistently, iNOS-GC pathway inhibitors blocked mitogen-activated protein kinase-ERK1/2 phosphorylation, which was required to mediate PGE2 functions. In vivo, in A431 cells implanted in nude mice, GC inhibition also decreased the tumor proliferation index and ERK1/2 activation. PGE2 effects were confined to the selective stimulation of the EP2 receptor subtype, leading to epidermal growth factor receptor (EGFR) transactivation via protein kinase A (PKA) and c-Src activation. EP2-mediated ERK1/2 activation and cell functions were abolished by inhibitors of PKA, c-Src, and EGFR, as well as by inhibiting iNOS pathway. Silencing of iNOS also impaired EGFR-induced ERK1/2 phosphorylation. These results indicate that iNOS/GC signaling is a downstream player in the control of EP2/EGFR-mediated tumor cell proliferation and invasion.