Background: Insulin-like growth factor (IGF)-I signalling stimulates proliferation, survival, and invasion in malignant mesothelioma and other tumour types. Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation. Methods: The effect of IGF stimulation on cap-mediated translation activation in mesothelioma cell lines was studied using binding assays to a synthetic 7-methyl GTP-cap analogue. In addition, cap-mediated translation was genetically repressed in these cells with a dominant active motive of 4E-BP1.Results: In most mesothelioma cell lines, IGF-I stimulation resulted in a hyperphosphorylation-mediated inactivation of 4E-BP1 compared with that in normal mesothelial cells. An inhibitor of Akt diminished IGF-I-mediated phosphorylation of 4E-BP1, whereas inhibiting MAPK signalling had no such effect. IGF-I stimulation resulted in the activation of the cap-mediated translation complex as indicated by an increased eIF4GeIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4GeIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1 A37A46) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1A37A46 repressor protein showed abrogated tumourigenicity compared with control tumours. Conclusion: IGF-I signalling in mesothelioma cells drives cell proliferation, motility, and tumourigenesis through its ability to activate cap-mediated protein translation complex through PI3KAktmTOR signalling.
Bibliographical noteFunding Information:
We thank Douglas Yee and Deepali Sachdev for their helpful advice and comments. We thank Michael Franklin for editorial assistance with this article. This work is supported in part by a grant from the Mesothelioma Applied Research Foundation (RAK).