PGE2/EP3/SRC signaling induces EGFR nuclear translocation and growth through EGFR ligands release in lung adenocarcinoma cells

// Lorenzo Bazzani 1, 2 , Sandra Donnini 1 , Federica Finetti 1 , Gerhard Christofori 2 , Marina Ziche 1 1 Department of Life Sciences, University of Siena, 53100, Siena, Italy 2 Department of Biomedizin, University of Basel, 4058, Basel, Switzerland Correspondence to: Marina Ziche, email: marina.ziche@unisi.it Keywords: nuclear EGFR, PGE 2 , EP3, EGFR ligands, lung cancer Received: October 12, 2016 Accepted: March 01, 2017 Published: March 10, 2017 ABSTRACT Prostaglandin E 2 (PGE 2 ) interacts with tyrosine kinases receptor signaling in both tumor and stromal cells supporting tumor progression. Here we demonstrate that in non-small cell lung carcinoma (NSCLC) cells, A549 and GLC82, PGE 2 promotes nuclear translocation of epidermal growth factor receptor (nEGFR), affects gene expression and induces cell growth. Indeed, cyclin D1, COX-2, iNOS and c-Myc mRNA levels are upregulated following PGE 2 treatment. The nuclear localization sequence (NLS) of EGFR as well as its tyrosine kinase activity are required for the effect of PGE 2 on nEGFR and downstream signaling activities. PGE 2 binds its bona fide receptor EP3 which by activating SRC family kinases, induces ADAMs activation which, in turn, releases EGFR-ligands from the cell membrane and promotes nEGFR. Amphiregulin (AREG) and Epiregulin (EREG) appear to be involved in nEGFR promoted by the PGE 2 /EP3-SRC axis. Pharmacological inhibition or silencing of the PGE 2 /EP3/SRC-ADAMs signaling axis or EGFR ligands i.e. AREG and EREG expression abolishes nEGFR induced by PGE 2 . In conclusion, PGE 2 induces NSCLC cell proliferation by EP3 receptor, SRC-ADAMs activation, EGFR ligands shedding and finally, phosphorylation and nEGFR. Since nuclear EGFR is a hallmark of cancer aggressiveness, our findings reveal a novel mechanism for the contribution of PGE 2 to tumor progression.