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Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer
S R C McCracken1, A Ramsay, R Heer
1Urology Research Group, Northern Institute for Cancer Research, University of Newcastle, Tyne and Wear, UK.
Abstract:
Abnormal intracellular signaling contributes to carcinogenesis and may represent novel therapeutic targets. mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) overexpression is associated with aggressive prostate cancer. In this study, we examined the role of extracellular signal-regulated kinase (ERK5, an MAPK and specific substrate for MEK5) in prostate cancer. ERK5 immunoreactivity was significantly upregulated in high-grade prostate cancer when compared to benign prostatic hyperplasia (P<0.0001). Increased ERK5 cytoplasmic signals correlated closely with Gleason sum score (P<0.0001), bony metastases (P=0.0044) and locally advanced disease at diagnosis (P=0.0023), with a weak association with shorter disease-specific survival (P=0.036). A subgroup of patients showed strong nuclear ERK5 localization, which correlated with poor disease-specific survival and, on multivariant analysis, was an independent prognostic factor (P<0.0001). Analysis of ERK5 expression in matched tumor pairs (before and after hormone relapse, n=26) revealed ERK5 nuclear expression was significantly associated with hormone-insensitive disease (P=0.0078). Similarly, ERK5 protein expression was increased in an androgen-independent LNCaP subline. We obtained the following in vitro and in vivo evidence to support the above expression data: (1) cotransfection of ERK5wt and MEK5D constructs in PC3 cells results in predominant ERK5 nuclear localization, similar to that observed in aggressive clinical disease; (2) ERK5-overexpressing PC3 cells have enhanced proliferative, migrative and invasive capabilities in vitro (P<0.0001), and were dramatically more efficient in forming tumors, with a shorter mean time for tumors to reach a critical volume of 1000 mm(3), in vivo (P<0.0001); (3) the MEK1 inhibitor, PD184352, blocking ERK1/2 activation at low dose, did not suppress proliferation but did significantly decrease proliferation at a higher dose required to inhibit ERK5 activation. Taken together, our results establish the potential importance of ERK5 in aggressive prostate cancer.
Insights
Extracellular signal-regulated kinase 5 (ERK5) is upregulated in aggressive prostate cancer, correlating with advanced disease and poor survival. Nuclear ERK5 is an independent prognostic factor, suggesting its potential as a therapeutic target in hormone-insensitive prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Abnormal intracellular signaling pathways are implicated in cancer development.
- Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) overexpression is linked to aggressive prostate cancer.
- Extracellular signal-regulated kinase (ERK5), a specific substrate for MEK5, is a key component of the MAPK pathway.
Purpose of the Study:
- To investigate the role of ERK5 in prostate cancer progression and its potential as a therapeutic target.
- To correlate ERK5 expression levels and localization with clinical parameters of prostate cancer aggressiveness.
- To evaluate the functional impact of ERK5 in prostate cancer cell behavior in vitro and in vivo.
Main Methods:
- Immunohistochemical analysis of ERK5 expression in prostate cancer tissues and benign prostatic hyperplasia.
- Correlation of ERK5 expression with clinical data including Gleason score, metastasis, and survival.
- In vitro studies using prostate cancer cell lines (PC3, LNCaP) to assess proliferation, migration, and invasion.
- In vivo tumor formation assays in immunocompromised mice.
- Pharmacological inhibition of ERK5 using MEK inhibitors.
Main Results:
- ERK5 immunoreactivity was significantly upregulated in high-grade prostate cancer compared to benign tissue.
- Increased ERK5 cytoplasmic signals correlated with higher Gleason scores, bony metastases, and locally advanced disease.
- Strong nuclear ERK5 localization was associated with poor disease-specific survival and identified as an independent prognostic factor.
- Nuclear ERK5 expression was significantly linked to hormone-insensitive prostate cancer.
- ERK5 overexpression enhanced prostate cancer cell proliferation, migration, and invasion in vitro and tumor growth in vivo.
- Inhibition of ERK5 activation significantly decreased proliferation in prostate cancer cells.
Conclusions:
- ERK5 is significantly upregulated in aggressive prostate cancer, with nuclear localization being a marker of poor prognosis.
- ERK5 plays a crucial role in promoting prostate cancer cell proliferation, migration, invasion, and tumor growth.
- ERK5 represents a potential therapeutic target for aggressive and hormone-insensitive prostate cancer.
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