Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer

McCracken, Stuart; Ramsay, Alison; Heer, Rakesh; Mathers, Marie E.; Jenkins, Benjamin; Edwards, Joanne; Robson, CN; Marquez, Rodolfo; Cohen, Philip; Leung, Hing Y.

doi:10.1038/sj.onc.1210963

Cited by 75 publications

(95 citation statements)

References 33 publications

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“…The mitogen-activated protein kinase Erk5 participates in animal development, and its deregulation has been linked to the aggressiveness of breast and prostate cancer (McCracken et al, 2008;Montero et al, 2009). Activation of Erk5 involves dual ) was generated, transfected and its response to nocodazole treatment analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…More recently another MAPK, termed Erk5 or BMK1 (big MAP kinase 1) has also been associated to the control of cellular proliferation in response to proliferative signals, cytokines and cellular stresses (Kato et al, 1997;Kato et al, 1998). Hyperactivation of the Erk5 pathway has been associated with highly aggressive forms of breast and prostate cancers (EsparisOgando et al, 2002;McCracken et al, 2008;Mehta et al, 2003;Montero et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Multisite phosphorylation of Erk5 in mitosis

Dı́az-Rodrı́guez

Pandiella

2010

Journal of Cell Science

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SummaryThe MAP kinase Erk5 plays important roles in cellular proliferation, and has recently been implicated in the regulation of mitosis. The classic pathway of Erk5 activation involves dual phosphorylation at its TEY microdomain by the upstream regulating kinase MEK5. Here we describe a second pathway that controls Erk5 phosphorylation. This pathway is activated in mitotic cells and involves kinase activities distinct from MEK5. Studies aimed at identifying these kinases suggested that CDK1 activity is required to sustain Erk5 phosphorylation in mitosis, as treatment with RO3306, a CDK1 inhibitor, reversed mitotic phosphorylation of Erk5. Moreover, CDK1 co-precipitated with Erk5 in mitotic cells. The mitotic phosphorylation of Erk5 occurs at multiple sites located at its unique C-terminal region, within an Erk5 subdomain that has formerly been implicated in the control of the subcellular location of Erk5. Furthermore, molecular studies indicated that phosphorylation at these sites may participate in the control of the transit of Erk5 between the cytosol and the nucleus, in addition to regulating its transcriptional activity. Together, our results demonstrate the existence of a second Erk5 phosphorylation pathway, that is activated in mitosis, and that may participate in the regulation of Erk5 functions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multisite phosphorylation of Erk5 in mitosis

Dı́az-Rodrı́guez

Pandiella

2010

Journal of Cell Science

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“…Western blot and immunohistochemistry experiments were done as described previously (12). Tissue microarray of prostate cancer biopsies, consisting of n = 24 benign and 43 cancer specimens, was prepared with local ethical committee approval.…”

Section: Eg5 Expression By Western Blot Analysis and Immunohistochemimentioning

confidence: 99%

Docetaxel-Resistant Prostate Cancer Cells Remain Sensitive toS-Trityl-l-Cysteine–Mediated Eg5 Inhibition

Wiltshire

Singh

Stockley

et al. 2010

Molecular Cancer Therapeutics

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Castrate-resistant prostate cancer remains a major clinical challenge. Due to the toxicity profile of taxane-based chemotherapy and treatment failure in some patients, novel agents with improved efficacy to side effect profiles are urgently needed. Eg5, a member of the kinesin-5 family, controls the formation of the bipolar spindle during cell division, and suppressed Eg5 function leads to mitotic arrest. S-Trityl-Lcysteine (STLC) is a novel Eg5-specific small-molecule inhibitor. Here, we report the first study to evaluate its use in prostate cancer. In a panel of prostate cancer cells, LNCaP and PC3 cells were the most and least sensitive to STLC treatment, with a 7.2-fold difference in their respective GI 50 values: 250 nmol/L and 1.8 μmol/L. In LNCaP cells, treatment with either STLC or docetaxel resulted in transient G 2 -M arrest and subsequent caspase-mediated cell death. However, STLC-and docetaxel-treated PC3M cells have distinct fates: STLC induced a transient G 2 -M arrest, followed by polyploidy; in contrast, docetaxel-treated PC3M cells progressed to apoptosis after a transient G 2 -M arrest. Docetaxel-resistant LNCaP-derived (LDocR) cells respond to STLC in a similar manner to the parental cells. Although the docetaxel-resistant PC3M-derived (PDocR) cell line and its parental PC3M cells have similar GI 50 to STLC treatment, PDocR cells showed significantly more G 2 -M arrest and less apoptosis. Hence, although docetaxel-resistant prostate cancer cells remain responsive to Eg5 inhibition with STLC, there are key differences at the cell cycle level, which may have implication in future development.

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“…In this regard, several possibilities can be considered, including other mechanisms to explain high expression levels of ERK5, for instance deregulated tyr-kinase activity [25]. However, a relationship has been found between the ERK5 signaling pathway and the prognosis of CCRCC [7], as well as other types of tumors (e.g., colon, breast, or prostate) [26][27][28], such that increased expression of this protein is associated with poorer prognosis (more advanced stages and presence of metastasis), as reported in the current study. Consequently, we can consider that ERK5 expression may be useful as a prognostic and perhaps therapeutic marker.…”

Section: Discussionmentioning

confidence: 99%

Implication of VHL, ERK5, and HIF-1alpha in clear cell renal cell carcinoma: Molecular basis

Serrano-Oviedo

Giménez-Bachs

Nam-Cha

et al. 2017

Urologic Oncology: Seminars and Original Investigations

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Objectives: To determine the expression status of several proteins related to VHL gene function and its relationship with common clinicopathological parameters.Material and methods: Observational, analytical, cross-sectional study with 50 patients diagnosed with clear cell renal cell carcinoma. The study analyzed VHL mutations and hypermethylation as well as protein expression of VHL, CA-IX, HIF-1alpha, VEGF, ERK1/2, and ERK5, relating them to clinical variables.A bivariate and multivariate descriptive logistical regression analysis was performed, using the presence of metastasis at diagnosis as dependent variable.Results: The study identified 13 (26%) VHL mutations related to nuclear grade (P ¼ 0.036). VHL hypermethylation was found in 20% of cases. VHL expression was associated with the presence of mutations (P ¼ 0.013), and the absence of expression was associated with nuclear grade and the presence of metastasis (P o 0.05). HIF-1alpha was negative in only 5 cases. Vascular endothelial growth factor (VEGF) was positive in 31 of 47 cases and was associated with Fuhrman nuclear grade, presence of metastasis, and stage (P o 0.05). ERK5 expression was increased in 58% of cases and associated with the presence of metastasis and more advanced stages (P o 0.05). In the logistic regression analysis, the only variable remaining in the model was VEGF expression (P ¼ 0.014).Conclusions: VEGF has prognostic value in clear cell renal cell carcinoma, and ERK5 may be a new prognostic marker in this type of tumor owing to its relationship with metastasis and more advanced stages. r

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Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer

Cited by 75 publications

References 33 publications

Multisite phosphorylation of Erk5 in mitosis

Multisite phosphorylation of Erk5 in mitosis

Docetaxel-Resistant Prostate Cancer Cells Remain Sensitive toS-Trityl-l-Cysteine–Mediated Eg5 Inhibition

Implication of VHL, ERK5, and HIF-1alpha in clear cell renal cell carcinoma: Molecular basis

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