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PGE2/EP3/SRC signaling induces EGFR nuclear translocation and growth through EGFR ligands release in lung adenocarcinoma cells
Journal
Oncotarget
Volume
8
Number
19
Pages / Article-Number
31270-31287
Mesh terms
Adenocarcinoma, pathology; Adenocarcinoma of Lung; Cell Line, Tumor; Cell Proliferation; Cyclic AMP-Dependent Protein Kinases, metabolism; Dinoprostone, metabolism; ErbB Receptors, metabolism; Gene Expression Regulation, Neoplastic; Humans; Ligands; Lung Neoplasms, pathology; Protein Binding; Protein Kinase C, metabolism; Protein Transport; Proto-Oncogene Proteins c-akt, metabolism; Receptors, Prostaglandin E, EP3 Subtype, metabolism; Signal Transduction; src-Family Kinases, metabolism
Abstract
Prostaglandin E2 (PGE2) 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, PGE2 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 PGE2 treatment. The nuclear localization sequence (NLS) of EGFR as well as its tyrosine kinase activity are required for the effect of PGE2 on nEGFR and downstream signaling activities. PGE2 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 PGE2/EP3-SRC axis. Pharmacological inhibition or silencing of the PGE2/EP3/SRC-ADAMs signaling axis or EGFR ligands i.e. AREG and EREG expression abolishes nEGFR induced by PGE2. In conclusion, PGE2 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 PGE2 to tumor progression.
