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BMK1 kinase suppresses epithelial-mesenchymal transition through the Akt/GSK3? signaling pathway.

ABSTRACT: Epithelial-mesenchymal transition (EMT) plays a crucial role in the development of cancer metastasis. The mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase, c-jun-NH(2)-kinase, and p38 have been implicated in promoting EMT, but a role for the MAP kinase BMK1 has not been studied. Here, we report that BMK1 signaling suppresses EMT. BMK1 elevation augmented E-cadherin-mediated cell-cell adhesion, downregulated mesenchymal markers, and decreased cell motility. Conversely, BMK1 silencing attenuated E-cadherin-mediated cell-cell adhesion, upregulated mesenchymal markers, and stimulated cell motility. BMK1 depletion dramatically increased the accumulation of endogenous Snail in the nuclear compartment. Snail accumulation was mediated by Akt/GSK3? signaling, which was activated by a modulation in the expression of the mTOR inhibitor DEPTOR. In support of these observations, BMK1 depletion promoted metastasis in vivo. Together, our findings reveal a novel mechanism of EMT control via mTOR/Akt inhibition that suppresses cancer metastasis.

SUBMITTER: Chen R

PROVIDER: S-EPMC3306490 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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BMK1 kinase suppresses epithelial-mesenchymal transition through the Akt/GSK3β signaling pathway.

Chen Runqiang R Yang Qingkai Q Lee Jiing-Dwan JD

Cancer research 20120126 6

Epithelial-mesenchymal transition (EMT) plays a crucial role in the development of cancer metastasis. The mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase, c-jun-NH(2)-kinase, and p38 have been implicated in promoting EMT, but a role for the MAP kinase BMK1 has not been studied. Here, we report that BMK1 signaling suppresses EMT. BMK1 elevation augmented E-cadherin-mediated cell-cell adhesion, downregulated mesenchymal markers, and decreased cell motility. Conversely ...[more]

PMID: 22282661

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Project description:Bladder cancer (BLCA) is the 9th most common cancer of mortality. Autophagy and epithelial to mesenchymal transition (EMT) have an essential role in cancer invasion and metastasis. However, the relationship between autophagy and EMT is still poorly understood in BLCA. Functional enrichment and pathway network analysis were carried out. Comprehensive protein-protein interactions (PPI) networks were proposed to prioritize candidate autophagy-related genes. Furthermore, an autophagy-related signature and a nomogram model were established by integrating clinical information and this signature risk score to evaluate candidate autophagy-related genes. RAB14 expression and its association with pathological information and survival were evaluated in samples from TCGA dataset. Knocking down RAB14 in T24 cells was constructed, and immunofluorescence staining, transmission electron microscopy, immunohistochemistry and western blotting and a series of functional assays were performed to evaluate the migration, invasion, EMT and autophagy abilities of BLCA cells. The autophagy-related gene RAB14 was the only candidate gene identified by three kinds of analytic approaches. RAB14 was highly upregulated in BLCA and correlated with clinical outcomes based on TCGA BLCA datasets. Knocking down RAB14 was found to inhibit EMT and autophagy in T24 cells. RAB14 levels were positively related to those of LC3B and Beclin1, two genes with critical roles in the autophagy process, and the correlation was further confirmed in clinical tissue specimens by IHC and western blot analysis. In addition, RAB14-promoted EMT, migration, and invasion in T24 cells could be partially reversed by autophagy activator, rapamycin. The effects of RAB14 on autophagy was associated with level of p-Akt, indicating that they were possibly mediated via PI3K/AKT signaling. These findings indicated that autophagy-related gene RAB14-promoted EMT, migration and invasion of bladder cancer via the Akt-associated autophagic pathway.

Dataset Information

BMK1 kinase suppresses epithelial-mesenchymal transition through the Akt/GSK3? signaling pathway.

Publications

BMK1 kinase suppresses epithelial-mesenchymal transition through the Akt/GSK3β signaling pathway.

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