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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.

SUBMITTER: Ye Q

PROVIDER: S-EPMC3966979 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Ye Q Q Cai W W Zheng Y Y Evers B M BM She Q-B QB

Oncogene 20130429 14

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 eukary ...[more]

PMID: 23624914

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Project description:BackgroundCartilage oligomeric matrix protein (COMP) is known to promote fibrosis in skin, lung and liver. Emerging evidence shows that COMP plays critical roles in tumor development, including breast cancer, colon cancer and hepatocellular carcinoma (HCC). Nevertheless, the role of COMP in HCC proliferation and metastasis and its underlying mechanisms remain fully unclear.MethodsSerum COMP was determined by ELISA. Cell Counting Kit-8 and plate colony formation were performed to evaluate cell proliferation. Wound healing and transwell assays were used to determine migration and invasion of HCC cells. Western blotting and immunofluorescence were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers and MMPs in HCC cells. The in vivo role of COMP was evaluated using mouse models. We also measured effects of hepatic stellate cells (HSCs)-conditioned medium (CM) on HCC progression using transwell coculture system.ResultsHere, we found that serum COMP levels in HCC patients were significantly higher than those in healthy controls. Accordingly, high serum COMP levels in HCC patients significantly correlated with malignant clinical characteristics and poor clinical outcomes. Next, we investigated that recombinant human COMP protein (rCOMP) treatment resulted in increased abilities of proliferation, invasion and migration of HCC cells. Furthermore, rCOMP treatment enhanced proliferative and metastatic colonization of HCC cells in vivo. Mechanistically, CD36 receptor played an essential role in COMP-mediated HCC cell proliferation and metastasis. Functionally, COMP/CD36 signaling caused phosphorylation of ERK and AKT, resulting in the upregulation of tumor-progressive genes such as EMT markers, MMP-2/9, Slug and Twist in HCC cells. Interestingly, we revealed that COMP was secreted by HSCs. CM of LX2 cells with COMP knockdown showed weaker effects on the activation of MEK/ERK and PI3K/AKT signaling pathways in HCC cells compared to control CM.ConclusionsOur findings indicated that HSCs-derived COMP collaborated with CD36 and subsequently played an essential role in MEK/ERK and PI3K/AKT-mediated HCC progression. COMP might act as a promising target for the diagnosis and treatment of aggressive HCC.

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

Publications

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

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