title: ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer.
abstract: The mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase (MEK/ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are often concurrently activated by separate genetic alterations in colorectal cancer (CRC), which is associated with CRC progression and poor survival. However, how activating both pathways is required for CRC metastatic progression remains unclear. Our recent study showed that both ERK and AKT signaling are required to activate eukaryotic translation initiation factor 4E (eIF4E)-initiated cap-dependent translation via convergent regulation of the translational repressor 4E-binding protein 1 (4E-BP1) for maintaining CRC transformation. Here, we identified that the activation of cap-dependent translation by cooperative ERK and AKT signaling is critical for promotion of CRC motility and metastasis. In CRC cells with coexistent mutational activation of ERK and AKT pathways, inhibition of either MEK or AKT alone showed limited activity in inhibiting cell migration and invasion, but combined inhibition resulted in profound effects. Genetic blockade of the translation initiation complex by eIF4E knockdown or expression of a dominant active 4E-BP1 mutant effectively inhibited migration, invasion and metastasis of CRC cells, whereas overexpression of eIF4E or knockdown of 4E-BP1 had the opposite effect and markedly reduced their dependence on ERK and AKT signaling for cell motility. Mechanistically, we found that these effects were largely dependent on the increase in mammalian target of rapamycin complex 1 (mTORC1)-mediated survivin translation by ERK and AKT signaling. Despite the modest effect of survivin knockdown on tumor growth, reduction of the translationally regulated survivin profoundly inhibited motility and metastasis of CRC. These findings reveal a critical mechanism underlying the translational regulation of CRC metastatic progression, and suggest that targeting cap-dependent translation may provide a promising treatment strategy for advanced CRC.
authors.affiliation: 1] Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA [2] Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Ye
authors.affiliation: 1] Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA [2] Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Cai
authors.affiliation: 1] Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA [2] Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 1] Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA [2] Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Evers
authors.affiliation: 1] Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA [2] Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Q-B
authors.initials: QB
authors.lastname: She
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D009362:Neoplasm Metastasis; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C107489:BIRC5 protein, human; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C411571:EIF4ENIF1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D046912:Multiprotein Complexes; D029543:Nucleocytoplasmic Transport Proteins; D010750:Phosphoproteins; D000077022:Survivin; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases