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MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion

Lookup NU author(s): Dr Piyush Mehta, Benjamin Jenkins, Louise McCarthy, Dr Loveling Thilak, Professor Craig Robson, Professor David Neal, Professor Hing Leung


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The novel mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) pathway has been implicated in the regulation of cellular proliferation. MEK5 expression has been detected in prostate cancer cells, although the significance of the MEK5/ERK5 pathway in human prostate cancer has not been tested. We examined MEK5 expression in 127 cases of prostate cancer and 20 cases of benign prostatic hypertrophy (BPH) by immunohistochemistry and compared the results to clinical parameters. We demonstrated that MEK5 expression is increased in prostate cancer as compared to benign prostatic tissue. Strong MEK5 expression correlates with the presence of bony metastases and less favourable disease-specific survival. Furthermore, among the patients with high Gleason score of 8-10, MEK5 overexpression has an additional prognostic value in survival. MEK5 transfection experiments confirm its ability to induce proliferation (P<0.0001), motility (P=0.0001) and invasion in prostate cancer cells (P=0.0001). MEK5 expression drastically increased MMP-9, but not MMP-2 mRNA expression. Luciferase report assays suggest that the -670/MMP-9 promoter is upregulated by MEK5 and electromobility shift assay further suggests the involvement of activator protein-I (AP-1), but not the NF-κB, binding site in the MMP-9 promoter. Using an AP-1 luciferase construct, activation of MEK5 was confirmed to enhance AP-1 activities up to twofold. Taken together, our results establish MEK5 as a key signalling molecule associated with prostate carcinogenesis. As the MEK5/ERK5 interaction is highly specific, it represents a potential target of therapy.

Publication metadata

Author(s): Mehta, P. B., Jenkins, B. L., McCarthy, L., Thilak, L. K. T., Robson, C. N., Neal, D. E., Leung, H. Y.

Publication type: Article

Publication status: Published

Journal: Oncogene

Year: 2003

Volume: 22

Issue: 9

Pages: 1381-1389

Print publication date: 06/03/2003

ISSN (print): 0950-9232

ISSN (electronic): 1476-5594


DOI: 10.1038/sj.onc.1206154

PubMed id: 12618764


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