Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma

B. A. Jacobson, A. De, M. G. Kratzke, M. R. Patel, J. Jay-Dixon, B. A. Whitson, A. A. Sadiq, P. B. Bitterman, V. A. Polunovsky, R. A. Kratzke

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)424-431
Number of pages8
JournalBritish Journal of Cancer
Volume101
Issue number3
DOIs
StatePublished - Aug 4 2009

Bibliographical note

Funding 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).

Keywords

  • 4E-BP1
  • Cap-dependent
  • EIF4E
  • EIF4F
  • IGF-I
  • Translation

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