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


CONCLUSIONS
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.
Jacobson
B A
BA
Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
De
A
A
Kratzke
M G
MG
Patel
M R
MR
Jay-Dixon
J
J
Whitson
B A
BA
Sadiq
A A
AA
Bitterman
P B
PB
Polunovsky
V A
VA
Kratzke
R A
RA
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D039562:Eukaryotic Initiation Factor-4F / Q000502:physiology*; D039642:Eukaryotic Initiation Factors; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008654:Mesothelioma / Q000209:etiology* / Q000628:therapy; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D039381:RNA Cap-Binding Proteins; D012315:RNA Caps / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002867:Chromones; D039562:Eukaryotic Initiation Factor-4F; D039642:Eukaryotic Initiation Factors; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D039381:RNA Cap-Binding Proteins; D012315:RNA Caps; D017526:Receptor, IGF Type 1; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one