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

Our plain-English summary of Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells, by S. Avino, P. De Marco, F. Cirillo, et al (Oncotarget, 2016).

The study

• Authors: S. Avino, P. De Marco, F. Cirillo, M.F. Santolla, E.M. De Francesco, M.G. Perri, D. Rigiracciolo, V. Dolce, A. Belfiore, M. Maggiolini, R. Lappano, A. Vivacqua
• Journal: Oncotarget
• Published: 2016;7(33):52710-52728
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study of two human cancer cell lines: IST-MES1 malignant mesothelioma cells and A549 lung cancer cells. It did not involve patients, and asbestos was not tested; the authors mention asbestos only as background. The authors treated the cells with insulin-like growth factor-I (IGF-I), a growth signal, and traced which cell receptors carried its effects. IGF-I activated its own receptor (IGF-IR) and raised levels of another receptor, GPER, and the two receptors were found bound together. IGF-I also switched on genes linked to GPER (CTGF and EGR1) and genes linked to a collagen receptor, DDR1 (MATN-2, FBN-1, NOTCH 1 and HES-1). Silencing IGF-IR or GPER prevented both sets of gene changes, while a drug that blocks DDR1 prevented the rise in the DDR1-linked genes. Each of these steps also stopped IGF-I from increasing cell migration in both cell lines. The authors concluded that this three-receptor network could be considered in designing combined treatments for mesothelioma and lung cancer. They said further studies are needed to clarify whether the receptors form a single complex.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study using human cancer cell lines; most results are reported as the mean of three independent experiments, with p less than 0.05 counted as statistically significant
• Who was studied: Two human cancer cell lines: IST-MES1 malignant mesothelioma cells (provided by Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy) and A549 lung cancer cells (obtained from ATCC). No human subjects.
• Exposure: Cells were treated with 100 ng/ml IGF-I or 10 μg/ml type I collagen (COL1), alone or with 1 μM inhibitors (including a DDR1 inhibitor), or after silencing of IGF-IR or GPER. Asbestos was not tested.
• Main results:
  • In both cell lines, IGF-I activated (phosphorylated) IGF-IR and the signaling molecules ERK and p-38.
  • In IST-MES1 and A549 cells, IGF-I increased GPER at the mRNA and protein levels.
  • IGF-I triggered a direct interaction between IGF-IR and GPER in both cell lines.
  • IGF-I increased the GPER-linked genes CTGF and EGR1, and silencing either IGF-IR or GPER prevented these changes.
  • IGF-I stimulated the DDR1 target genes MATN-2, FBN-1, NOTCH 1 and HES-1. This was inhibited by the DDR1 inhibitor and by silencing IGF-IR or GPER.
  • In IST-MES1 mesothelioma cells, IGF-I and COL1 induced chemotactic motility (movement toward the signal), which was abolished by the DDR1 inhibitor. Similar A549 results were reported as data not shown.
  • In IST-MES1 and A549 cells, the DDR1 inhibitor abolished cell migration induced by IGF-I and by COL1.
  • In IST-MES1 and A549 cells, silencing IGF-IR or GPER abolished IGF-I-triggered cell migration in Boyden chamber assays.
• The authors' conclusion: The authors concluded that the signaling network between IGF-IR, GPER and DDR1 could be taken into account in designing combined treatment strategies for mesothelioma and lung cancers.
• Limitations the authors state:
  • The authors state that further studies are needed to clarify whether IGF-IR, DDR1 and GPER form a three-part (ternary) complex.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Lung Cancer, Collagen.

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