MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion.
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-kappa B, 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.
Mehta
P B
PB
Prostate Research Group, Department of Surgery, The Medical School, University of Newcastle-upon-Tyne, Framlington Place, UK.
Jenkins
B L
BL
McCarthy
L
L
Thilak
L
L
Robson
C N
CN
Neal
D E
DE
Leung
H Y
HY
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary*; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D003094:Collagen; D004338:Drug Combinations; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney; D007797:Laminin; D048671:MAP Kinase Kinase 5; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011470:Prostatic Hyperplasia / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D016019:Survival Analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D007797:Laminin; D009363:Neoplasm Proteins; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; C059485:matrigel; D003094:Collagen; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9