Research Papers: Pathology:
Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells
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Silvia Avino1,*, Paola De Marco1,*, Francesca Cirillo1, Maria Francesca Santolla1, Ernestina Marianna De Francesco1, Maria Grazia Perri1, Damiano Rigiracciolo1, Vincenza Dolce1, Antonino Belfiore2, Marcello Maggiolini1, Rosamaria Lappano1,** and Adele Vivacqua1,**
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
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
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.
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