Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells

// Silvia Avino 1,* , Paola De Marco 1,* , Francesca Cirillo 1 , Maria Francesca Santolla 1 , Ernestina Marianna De Francesco 1 , Maria Grazia Perri 1 , Damiano Rigiracciolo 1 , Vincenza Dolce 1 , Antonino Belfiore 2 , Marcello Maggiolini 1 , Rosamaria Lappano 1,** and Adele Vivacqua 1,** 1 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy 2 Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy * These authors have contributed equally to this work ** Joint senior Authors Correspondence to: Marcello Maggiolini, email: // Keywords : DDR1, GPER, IGF-I, IGF-IR, mesothelioma, lung cancer, Pathology Section Received : April 06, 2016 Accepted : June 17, 2016 Published : June 30, 2016 Abstract Insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) system has been largely involved in the pathogenesis and development of various tumors. We have previously demonstrated that IGF-IR cooperates with the G-protein estrogen receptor (GPER) and the collagen receptor discoidin domain 1 (DDR1) that are implicated in cancer progression. Here, we provide novel evidence regarding the molecular mechanisms through which IGF-I/IGF-IR signaling triggers a functional cross-talk with GPER and DDR1 in both mesothelioma and lung cancer cells. In particular, we show that IGF-I activates the transduction network mediated by IGF-IR leading to the up-regulation of GPER and its main target genes CTGF and EGR1 as well as the induction of DDR1 target genes like MATN-2, FBN-1, NOTCH 1 and HES-1. Of note, certain DDR1-mediated effects upon IGF-I stimulation required both IGF-IR and GPER as determined knocking-down the expression of these receptors. The aforementioned findings were nicely recapitulated in important biological outcomes like IGF-I promoted chemotaxis and migration of both mesothelioma and lung cancer cells. Overall, our data suggest that IGF-I/IGF-IR system triggers stimulatory actions through both GPER and DDR1 in aggressive tumors as mesothelioma and lung tumors. Hence, this novel signaling pathway may represent a further target in setting innovative anticancer strategies.