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Epidermal Growth Factor Facilitates Epinephrine Inhibition of P2X₇-Receptor-Mediated Pore Formation and Apoptosis: A Novel Signaling Network

Departments of Pharmacology (L.W., Y.-H.F.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; and Departments of Reproductive Biology (G.I.G.), Physiology and Biophysics (G.I.G.), and Oncology (G.I.G.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: George I. Gorodeski, M.D., Ph.D., University MacDonald Women’s Hospital, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: gig{at}cwru.edu.

Epidermal growth factor (EGF), epinephrine, and the P2X₇ receptor system regulate growth of human uterine cervical epithelial cells, but little is known about how these systems intercommunicate in exerting their actions. The objective of this study was to understand the mechanisms of EGF and epinephrine regulation of growth of cervical cells. Treatment of cultured CaSki cells with 0.2 nM EGF increased cell number via a PD98059-sensitive pathway. Treatment with 2 nM epinephrine increased cell number, and the effect was facilitated by cotreatment with EGF. Whereas the effect of EGF alone involved up-regulation of [³H]-thymidine incorporation and an increase in cell proliferation, the effect of epinephrine was mediated by inhibition of apoptosis. Epinephrine inhibited apoptosis induced by the P2X₇ receptor ligand 2',3'-0-(4-benzoylbenzoyl)-ATP, by attenuation of P2X₇ receptor plasma membrane pore formation. Cotreatment with EGF facilitated epinephrine effect via a phosphoinositide 3-kinase-dependent mechanism. CaSki cells express the ß2-adrenoceptor, and the epinephrine antiapoptotic effect could be mimicked by ß2-adrenoceptor agonists and by activators of adenylyl cyclase. Likewise, the effect could be blocked by ß2-adrenoceptor blockers and by the inhibitor of protein kinase-A H-89. Western immunoblot analysis revealed that epinephrine decreased the levels of the glycosylated 85-kDa form of the P2X₇ receptor and increased receptor degradation, and that EGF potentiated these effects of epinephrine. EGF did not affect cellular levels of the ß2-adrenoceptor. In contrast, EGF, acting via the EGF receptor, augmented ß2-adrenoceptor recycling, and it inhibited ß2-adrenoceptor internalization via a phosphoinositide 3-kinase-dependent mechanism. We conclude that, in cervical epithelial cells, EGF has a dual role: as mitogen, acting via the MAPK/MAPK kinase pathway, and as an antiapoptotic factor by facilitating epinephrine effect and resulting in greater expression of ß2-adrenoceptors in the plasma membrane. These findings underscore a novel signaling network of communication between the receptor tyrosine kinases, the G protein-coupled receptors, and the purinergic P2X₇ receptor.

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