ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer

Abstract

The MEK/ERK and 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 eIF4E-initiated cap-dependent translation via convergent regulation of the translational repressor 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 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.

Evaluation of spheroid head and neck squamous cell carcinoma cell models in comparison to monolayer cultures

“…The three cell lines were stained for Ki-67, vascular endothelial growth factor receptor (VEGFR), EGF receptor (EGFR) and survivin. Ki-67 serves as a proliferation marker (22), VEGFR is an (lymph) angiogenesis receptor (23), EGFR is a member of the Her/ erbB receptor family and an important receptor tyrosine kinase in HNSCC (24), and survivin is described as an apoptotic inhibitory protein (25). Primary antibodies for Ki-67 (monoclonal rabbit antibody; Abcam, Cambridge, MA, USA; dilution, 1:400), VEGFR (polyclonal rabbit antibody; Sigma-Aldrich; dilution, 1:100), EGFR (monoclonal rabbit antibody; Abcam; dilution, 1:100) and survivin (monoclonal rabbit antibody; Abcam; dilution, 1:500) were applied for 60 min.…”

Colorectal cancer carcinogenesis: a review of mechanisms

“…The activated PI3K further activates AKT1 and AKT2, which then enhances tumor growth by promoting epithelial to mesenchymal transition (EMT) 52,53 . Loss-of-function mutations in PTEN, which is a tumor suppressor and an antagonist of the PI3K/AKT pathway, induce AKT-regulated metastasis in CRCs 54 . The MEK/ERK and PI3K/AKT pathways often converge to activate a cap-dependent translation through survivin knockdown, which can inhibit metastasis 55 .…”

Inhibitor of DNA-binding protein 1 knockdown arrests the growth of colorectal cancer cells and suppresses hepatic metastasis in vivo

“…This can be interpreted along with recent studies of the tumorigenic effect of ID1 in keratinocytes (22) and in a variety of human tumors (23,24), which suggest that an elevated ID1 protein level may promote cell proliferation, inhibit cellular apoptosis, and repress differentiation, thereby leading to the onset and progression of CRC. Since survivin was reported to be a downstream regulator in the ID1/PI3K/Akt/NF-κB/survivin signaling pathway for endothelial progenitor cell proliferation, and CRC tumor growth and malignant metastasis (25,26), the fact that ID1 knockdown induced a decrease in survivin expression, may indicate that activation of survivin is a consequence of the expression of ID1 in CRC cell lines. It has been suggested that PCNA is a proliferation marker of tumors and is critical for DNA synthesis (27).…”