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 (Po0.0001), motility (P ¼ 0.0001) and invasion in prostate cancer cells (P ¼ 0.0001). MEK5 expression drastically increased MMP-9, but not MMP-2 mRNA expression. Luciferase report assays suggest that the À670/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-jB, 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.

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FGF7/Keratinocyte growth factor (KGF) regulates the dierentiation and development of the prostate epithelium, while over-expression of FGF8 and FGF1 are implicated in carcinogenesis of the prostate. We tested the hypothesis that dierent members of the FGF family function through dierent signalling molecules. In prostate DU145 cells, both FGF1 and FGF2 activated ERK1/2 potently and p38 moderately. KGF was however most ecient in inducing p38 activities but had no eect on ERK1/2 function. JNK and STAT activities were not induced by FGFs in prostate cells. In vitro expression of the transcription factors Elk-1 and MEF2A (substrates for ERK1/2 and p38, respectively) for functional quanti®cation, con®rmed the pattern of FGF-induced MAPK activations in COS-7 cells. Furthermore, KGF was more ecient than FGF1 and FGF2 in inducing actin stress ®bres, and the speci®c p38 inhibitor SB202190 completely abolished this in a dose-dependent manner. The MEK1/2 inhibitor, U0126, had no eect on FGF-induced stress ®bre formation. This study demonstrates the selective activation of MAPK family members by FGFs resulting in activation of transcription factors and stress ®bre formation. As multiple FGFs are overexpressed in human prostate cancer, characterization of the distinct signalling pathway by FGFs may reveal new speci®c targets for therapy. Oncogene (2001) 20, 5359 ± 5365.

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