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

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 eIF4G/eIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4G/eIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1(A37/A46)) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1(A37/A46) 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 PI3K/Akt/mTOR signalling.

• Authors: 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
• Journal: British journal of cancer (Br J Cancer) Vol. 101 Issue 3 Pg. 424-31 (Aug 04 2009) ISSN: 1532-1827 [Electronic] England
• PMID: 19603014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Cell Cycle Proteins
• Chromones
• EIF4EBP1 protein, human
• Eif4ebp1 protein, mouse
• Eukaryotic Initiation Factor-4F
• Eukaryotic Initiation Factors
• Morpholines
• Phosphoproteins
• RNA Cap-Binding Proteins
• RNA Caps
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt

Topics

• Adaptor Proteins, Signal Transducing (physiology)
• Animals
• Carrier Proteins (physiology)
• Cell Cycle Proteins
• Cell Line, Tumor
• Chromones (pharmacology)
• Eukaryotic Initiation Factor-4F (physiology)
• Eukaryotic Initiation Factors
• Humans
• Insulin-Like Growth Factor I (physiology)
• Mesothelioma (etiology, therapy)
• Mice
• Morpholines (pharmacology)
• Neoplasm Transplantation
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphoproteins (physiology)
• Protein Biosynthesis
• Proto-Oncogene Proteins c-akt (physiology)
• RNA Cap-Binding Proteins
• RNA Caps (physiology)
• Receptor, IGF Type 1 (physiology)
• Signal Transduction
• Transplantation, Heterologous