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Lookup NU author(s): Dr Stuart McCracken
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BACKGROUND: Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)-extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised. METHODS: Modulation of ERK5 expression or function in human PCa PC3 and PC3-ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT-PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry. RESULTS: Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P < 0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P = 0.013 and P < 0.0001, respectively). CONCLUSION: Our in vitro, in vivo and clinical data support an important role for the MEK5-ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa. British Journal of Cancer (2011) 104, 664-672. doi:10.1038/sj.bjc.6606062 www.bjcancer.com Published online 25 January 2011 (C) 2011 Cancer Research UK
Author(s): Ramsay AK, McCracken SRC, Soofi M, Fleming J, Yu AX, Ahmad I, Morland R, Machesky L, Nixon C, Edwards DR, Nuttall RK, Seywright M, Marquez R, Keller E, Leung HY
Publication type: Article
Publication status: Published
Journal: British Journal of Cancer
Year: 2011
Volume: 104
Issue: 4
Pages: 664-672
Print publication date: 25/01/2011
ISSN (print): 0007-0920
ISSN (electronic): 1532-1827
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/sj.bjc.6606062
DOI: 10.1038/sj.bjc.6606062
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