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.
|Number of pages||12|
|State||Published - Apr 3 2014|
Bibliographical noteFunding Information:
We thank Drs Rina Plattner and Kathleen O’Connor and Ms Donna Gilbreath for critical reading and editing of this manuscript, Dr Ronald Blasberg for providing the SFG-FLuc-IRES2-GFP construct. Dr Piotr Rychahou for the assistance in the animal experiments, and Ms Dana Napier for the histologic tissue processing. This work was supported by grants from NCI (R01CA175105 to Q-B She, P30CA147886 and Gastrointestinal Cancer SPORE P20CA150343 to BM Evers), ACS (IRG85-001-22 to Q-B She), NIH/NCATS UL1RR033173 (KL2RR0033171 to Q-B She), and the Markey Cancer Center Start-up fund (to Q-B She).
- Colorectal cancer
- Translational regulation
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research