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EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways
Author(s) -
Donnini Sandra,
Finetti Federica,
Solito Raffaella,
Terzuoli Erika,
Sacchetti Andrea,
Morbidelli Lucia,
Patrignani Paola,
Ziche Marina
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7581com
Subject(s) - transactivation , prostaglandin e2 receptor , cancer research , epidermal growth factor receptor , cell growth , epidermal growth factor , signal transduction , a431 cells , mapk/erk pathway , chemistry , biology , microbiology and biotechnology , receptor , cell , oncogene , cell cycle , transcription factor , biochemistry , agonist , gene
ABSTRACT In squamous cell carcinoma, the levels of nitric oxide (NO) derived from inducible NO synthase (iNOS) and prostaglandin E 2 (PGE 2 ) 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 PGE 2 ‐mediated tumor invasiveness and proliferation in squamous cell carcinoma, A431, and SCC‐9 cells. Cell invasion and proliferation promoted by PGE 2 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 PGE 2 functions. In vivo , in A431 cells implanted in nude mice, GC inhibition also decreased the tumor proliferation index and ERK1/2 activation. PGE 2 effects were confined to the selective stimulation of the EP2 receptor subtype, leading to epidermal growth factor receptor (EGFR) transactivation via protein ki‐nase 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 down‐stream player in the control of EP2/EGFR‐mediated tumor cell proliferation and invasion.—Donnini, S., Finetti, F., Solito, R., Terzuoli, E., Sacchetti, A., Morbidelli, L., Patrignani, P., Ziche, M. EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways. FASEB J. 21, 2418–2430 (2007)