ERK5 signalling in prostate cancer promotes an invasive phenotype

• Published in: British journal of cancer Vol. 104; no. 4; pp. 664 - 672
• Main Authors: Ramsay, A K, McCracken, S R C, Soofi, M, Fleming, J, Yu, A X, Ahmad, I, Morland, R, Machesky, L, Nixon, C, Edwards, D R, Nuttall, R K, Seywright, M, Marquez, R, Keller, E, Leung, H Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.02.2011; Nature Publishing Group
• Subjects: 631/80/84/2336; 631/80/86; 692/699/67/589/466; Androgens; Animals; Benzamides - pharmacology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Cell growth; Cell Movement - drug effects; Cell Movement - genetics; Cell Proliferation - drug effects; Cells, Cultured; Drug Evaluation, Preclinical; Drug Resistance; Epidemiology; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Genotype & phenotype; Humans; Kinases; Male; MAP Kinase Kinase 5 - genetics; MAP Kinase Kinase 5 - metabolism; MAP Kinase Kinase 5 - physiology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - physiology; Medical prognosis; Medical research; Medical sciences; Metastasis; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 7 - genetics; Mitogen-Activated Protein Kinase 7 - metabolism; Mitogen-Activated Protein Kinase 7 - physiology; Molecular Diagnostics; Molecular Medicine; Motility; Neoplasm Invasiveness; Nephrology. Urinary tract diseases; Oncology; Phenotype; Prostate cancer; Prostatic Hyperplasia - genetics; Prostatic Hyperplasia - metabolism; Prostatic Hyperplasia - pathology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Proteins; RNA, Small Interfering - pharmacology; Transfection; Transplantation, Heterologous; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; United Kingdom > UK; United States > US; invasive phenotype; prostate cancer; signalling; Urinary system disease; Prostate disease; Malignant tumor; Signal transduction; Extracellular signal-regulated protein kinase 5; Phenotype; Cancerology; Invasive cancer; Male genital diseases; Prostate cancer; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6606062

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.