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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.
Highlights
Lung cancer is the most frequent cause of cancer incidence and mortality worldwide at least in part due to the increasing number of risk factors in diverse developing countries [1,2]
On the basis of previous studies showing that Insulin-like growth factor-I (IGF-I) triggers stimulatory effects in malignant mesothelioma as well as in lung cancer cells [31,32], we began our study evaluating the transduction signaling activated by insulin-like growth factors (IGFs)-I in IST-MES1 mesothelioma and A549 lung cancer cells, which were used as model system
On the basis of our previous data showing that IGF-I signaling cooperates with several G protein-coupled receptors (GPCRs) family members, including G-protein estrogen receptor (GPER), toward cancer progression [19, 25], we evaluated whether IGF-I regulates GPER expression in IST-MES1 and A549 cells
Summary
Lung cancer is the most frequent cause of cancer incidence and mortality worldwide at least in part due to the increasing number of risk factors in diverse developing countries [1,2]. Chronic inflammatory processes caused by the deposition of asbestos fibers and the subsequent release of cytokines and growth factors by macrophages and mesothelial cells have been shown to play an active role toward the development of both pleural MM and lung cancer [7,8] In this vein, the IGF system, the complex system involving the insulin-like growth factors (IGFs) and related receptors as well as IGF-binding proteins, has been established as an important regulator of tumor initiation www.impactjournals.com/oncotarget and progression in several malignancies, including pleural MM and lung cancer [9,10,11,12,13]. A dysregulated IGF system has been shown to be implicated in various chronic diseases, such as pulmonary fibrosis [17,18]
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