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

S. R. C. McCracken, A. Ramsay, R. Heer, M. E. Mathers, B. L. Jenkins, J. Edwards, C. N. Robson, R. Marquez, P. Cohen, H. Y. Leung (Lead / Corresponding author)

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    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 diseasespecific 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 mm(3), 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.

    Original languageEnglish
    Pages (from-to)2978-2988
    Number of pages11
    JournalOncogene
    Volume27
    Issue number21
    DOIs
    Publication statusPublished - 8 May 2008

    Keywords

    • prostate cancer
    • ERK5
    • MEK5
    • ACTIVATED PROTEIN-KINASE
    • RECEPTOR TYROSINE KINASES
    • EPIDERMAL-GROWTH-FACTOR
    • MAP KINASE
    • DIFFERENTIAL EXPRESSION
    • PATHWAY
    • PROLIFERATION
    • MICE

    Cite this

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