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

Oncogene volume 27, pages 2978–2988 (2008)Cite this article

Abstract

Abnormal intracellular signaling contributes to carcinogenesis and may represent novel therapeutic targets. mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) overexpression is associated with aggressive prostate cancer. In this study, we examined the role of extracellular signal-regulated kinase (ERK5, an MAPK and specific substrate for MEK5) in prostate cancer. ERK5 immunoreactivity was significantly upregulated in high-grade prostate cancer when compared to benign prostatic hyperplasia (P<0.0001). Increased ERK5 cytoplasmic signals correlated closely with Gleason sum score (P<0.0001), bony metastases (P=0.0044) and locally advanced disease at diagnosis (P=0.0023), with a weak association with shorter disease-specific survival (P=0.036). A subgroup of patients showed strong nuclear ERK5 localization, which correlated with poor disease-specific survival and, on multivariant analysis, was an independent prognostic factor (P<0.0001). Analysis of ERK5 expression in matched tumor pairs (before and after hormone relapse, n=26) revealed ERK5 nuclear expression was significantly associated with hormone-insensitive disease (P=0.0078). Similarly, ERK5 protein expression was increased in an androgen-independent LNCaP subline. We obtained the following in vitro and in vivo evidence to support the above expression data: (1) cotransfection of ERK5wt and MEK5D constructs in PC3 cells results in predominant ERK5 nuclear localization, similar to that observed in aggressive clinical disease; (2) ERK5-overexpressing PC3 cells have enhanced proliferative, migrative and invasive capabilities in vitro (P<0.0001), and were dramatically more efficient in forming tumors, with a shorter mean time for tumors to reach a critical volume of 1000 mm3, in vivo (P<0.0001); (3) the MEK1 inhibitor, PD184352, blocking ERK1/2 activation at low dose, did not suppress proliferation but did significantly decrease proliferation at a higher dose required to inhibit ERK5 activation. Taken together, our results establish the potential importance of ERK5 in aggressive prostate cancer.

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Acknowledgements

We thank Tom Fanshaw (MRC Department of Statistics, Cambridge University) who has reviewed our data, statistical methodology and validated the interpretation of our dataset. We also thank Prof Herbie Newell and Dr Huw Thomas for their expert help in setting up the in vivo mouse model. This work was supported by funding from the British Urological Foundation, the Dunhill Medical Trust/Royal College of Surgeons of England, Royal College of Physicians and Surgeons of Glasgow and NCRI PROMPT (G0100100/64424).

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Authors and Affiliations

  1. Urology Research Group, Northern Institute for Cancer Research, University of Newcastle, Tyne and Wear, UK

    S R C McCracken, R Heer, B L Jenkins, C N Robson & H Y Leung

  2. Cancer Research UK Laboratories, Beatson Institute for Cancer Research, Glasgow, UK

    A Ramsay & H Y Leung

  3. Division of Cancer Sciences and Molecular Pathology, Section of Surgical and Translational Research, University of Glasgow, Glasgow, UK

    A Ramsay, J Edwards & H Y Leung

  4. Department of Cellular Pathology, Royal Victoria Infirmary, Tyne and Wear, UK

    M E Mathers

  5. Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, UK

    R Marquez & P Cohen

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  1. S R C McCracken
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Correspondence to H Y Leung.

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Conflict of Interest

Supporting sources had no involvement in study design, in the collection, analysis or interpretation of data, in the writing of the report or in the decision to submit for publication.

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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McCracken, S., Ramsay, A., Heer, R. et al. Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer. Oncogene 27, 2978–2988 (2008). https://doi.org/10.1038/sj.onc.1210963

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