Modulation of ERK5 Is a Novel Mechanism by Which Cdc42 Regulates Migration of Breast Cancer Cells

Zuo, Yufeng; Wu, Yuexiu; Wehrli, Bret; Chakrabarti, Subrata; Chakraborty, Chandan

doi:10.1002/jcb.24950

Cited by 16 publications

(19 citation statements)

References 47 publications

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“…It was reported that knockdown of Cdc42 increased ERK5 phosphorylation and suppressed cell motility and invasion in moderately metastatic Hs-578T breast cancer cells, suggesting that ERK5 signaling negatively correlates with metastatic progression [91, 92]. However, Cdc42 depletion enhanced cell migration and invasion in highly aggressive MDA-MB-231 breast cancer cells [91].…”

Section: Role Of Mek5 Pathway In Metastatic Progressionmentioning

confidence: 99%

“…However, Cdc42 depletion enhanced cell migration and invasion in highly aggressive MDA-MB-231 breast cancer cells [91]. If activation of ERK5 associated with Cdc42 silencing, then ERK5 would exert pro-metastatic effects in these highly invasive cells; yet ERK5 activity was shown to decrease the invasive potential of MDA-MB-231 cells [92]. These conflicting results highlight the nuanced and cellular context-dependence of ERK5 function in modulating the invasive phenotype and further supports continued investigation of MEK-ERK5 signaling in regulation of metastatic progression.…”

Section: Role Of Mek5 Pathway In Metastatic Progressionmentioning

confidence: 99%

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Oncogenic signaling of MEK5-ERK5

et al. 2017

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Mitogen-activated protein kinases (MAPKs) regulate diverse cellular processes including proliferation, cell survival, differentiation, and apoptosis. While conventional MAPK constituents have well-defined roles in oncogenesis, the MAPK kinase 5-extracellular signal-regulated kinase 5 (MEK5-ERK5) pathway has only recently emerged in cancer research. In this review, we consider the MEK5 signaling cascade, focusing specifically on its involvement in drug resistance and regulation of aggressive cancer phenotypes. Moreover, we explore the role of MEK5 in tumorigenesis and metastatic progression, discussing the discrepancies in preclinical studies and assessing its viability as a therapeutic target for anti-cancer agents.

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Section: Role Of Mek5 Pathway In Metastatic Progressionmentioning

confidence: 99%

Section: Role Of Mek5 Pathway In Metastatic Progressionmentioning

confidence: 99%

Oncogenic signaling of MEK5-ERK5

et al. 2017

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“…Additional studies have suggested a differential regulatory role of ERK5 in EMT (25,26). The present study, to the best of our knowledge, is the first to investigate the role of ERK5 in TS-induced urocystic EMT in vivo.…”

Section: Introductionmentioning

confidence: 60%

“…Previous studies have indicated that ERK5 triggers the motility and invasive phenotype of cells (22)(23)(24). Additional studies have suggested a differential regulatory role of ERK5 in EMT (25,26). These reports have suggested that ERK5 regulation of EMT may be sensitive to cell type and/or the cellular microenvironment.…”

Section: Discussionmentioning

confidence: 98%

ERK5 regulates tobacco smoke-induced urocystic epithelial-mesenchymal transition in BALB/c mice

Min

Geng

Liu

et al. 2017

Molecular Medicine Reports

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Abstract. Tobacco smoke (TS) is an important risk factor of bladder cancer. Epithelial-mesenchymal transition (EMT) is involved in the initiation and development of cancer. The role of extracellular signal-regulated kinase (ERK) 5 in regulating TS-induced EMT remains to be elucidated. The aim of the present study was to investigate the regulatory role of ERK5 in TS-triggered EMT in the bladder of mice. BALB/c mice were used for an in vivo TS exposure model. Mice were treated for 6 h a day for 12 weeks. The results demonstrated that mice exposed to TS had decreased mRNA and protein expression levels of the epithelial markers E-cadherin and zonula occludens-1, whereas expression levels of the mesenchymal markers Vimentin and N-cadherin were increased. Treatment with XMD8-92, a highly specific ERK5 inhibitor, effectively abrogated TS-triggered activation of ERK5, activator protein-1 and EMT alterations in the bladder of BALB/c mice. The data suggested that ERK5 regulates TS-mediated urocystic EMT. These findings provide insight into the molecular mechanisms of TS-associated bladder tumorigenesis. IntroductionBladder cancer (BC) is the fifth most common type of malignant tumor worldwide (1) and one of the most frequently occurring in the urinary system. It is predominantly present in Europe, North America and Australia, with approximately 420,000 newly diagnosed cases each year and a leading cause of cancer-associated mortality (2,3). Of all urinary malignancies, BC is the primary cause of mortality in China (4,5).A number of studies have revealed that tobacco smoke (TS), the environment and diet are primary risk factors for BC, in addition to drinking water contaminants, including chlorinated byproducts and arsenic, the use of pioglitazone, obesity, hypertension and diabetes (2,6,7). A previous study reported that 23% of female and 50% of male BC cases have been attributed to TS (8). It has been reported that current tobacco smokers have a fourfold greater risk of developing BC, compared with non-smokers (9). Progress in the understanding of the molecular mechanisms underlying the initiation and progression of BC has been made; however, the molecular pathogenesis remains to be fully elucidated.Epithelial-mesenchymal transition (EMT) is an important mechanism in embryonic progression and cancer development (10). Cells progressively lose their epithelial characteristics and acquire mesenchymal features during the process of EMT (11). In addition to facilitating tumor invasion and metastasis, EMT is also involved in the initiation of tumorigenesis by promoting cell malignant transformation. TS has been previously demonstrated to promote the initial progression of . TS-triggered EMT has been revealed to regulate early events in carcinogenesis, including downregulation of E-cadherin, loss of cell-cell adhesion and increased mobility of cells. However, the underlying molecular mechanisms by which TS induces EMT remain to be fully elucidated.Extracellular signal-regulated kinase (ERK) 5 is the least studied member of the ...

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“…Remarkably, following knockdown of the MEK5/ERK5 pathway, tumour xenograft growth, metastasis, and the generation of tumour circulating cells was significantly reduced [35,38]. Nevertheless, in contrast with this body of data, a recent study reported that ERK5 expression was reduced in breast cancer tumour samples, correlating with a worse disease prognosis, and that ERK5 inhibition in MDA-MB-231 and Hs578 T breast cancer cell lines contributed to increased cell migration and invasion [39]. However, multiple additional studies demonstrated that ERK5 activation in MCF-7, MDA-MB-468, MDA-MB-453, and SKBR3 breast cancer cell lines promoted resistance to therapy, migration, and invasion [31,34,40,41], thus supporting ERK5 signalling as a potential therapeutic target in breast cancer.…”

Section: Breast Cancermentioning

confidence: 94%