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

McCracken, S.R.C., Ramsay, A., Heer, R., Mathers, M.E., Jenkins, B.L., Edwards, J. , Robson, C.N., Marquez, R., Cohen, P. and Leung, H.Y. (2008) Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer. Oncogene, 27(21), pp. 2978-2988. (doi:10.1038/sj.onc.1210963)

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Publisher's URL: http://dx.doi.org/10.1038/sj.onc.1210963

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 (<i>P</i><0.0001). Increased ERK5 cytoplasmic signals correlated closely with Gleason sum score (<i>P</i><0.0001), bony metastases (<i>P</i>=0.0044) and locally advanced disease at diagnosis (<i>P</i>=0.0023), with a weak association with shorter disease-specific survival (<i>P</i>=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 (<i>P</i><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 (<i>P</i>=0.0078). Similarly, ERK5 protein expression was increased in an androgen-independent LNCaP subline. We obtained the following <i>in vitro</i> and <i>in vivo</i> 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 (<i>P</i><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, <i>in vivo</i> (<i>P</i><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.

Item Type:Articles
Keywords:Prostate cancer, ERK5, MEK5
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leung, Professor Hing and Marquez, Dr Rudi and Edwards, Professor Joanne
Authors: McCracken, S.R.C., Ramsay, A., Heer, R., Mathers, M.E., Jenkins, B.L., Edwards, J., Robson, C.N., Marquez, R., Cohen, P., and Leung, H.Y.
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncogene
Publisher:Nature Publishing Group
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:10 December 2007
Copyright Holders:Copyright © 2008 Nature Publishing Group
First Published:First published in Oncogene 27:2978-2988
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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