Abstract
A current challenge in prostate cancer treatment is how to differentiate aggressive disease from indolent prostate cancer. There is an urgent need to identify markers that would accurately distinguish indolent prostate cancer from aggressive disease. The aim of this study was to evaluate the role of PDZ Domain-binding kinase (PBK) in prostate cancer and to determine if PBK expression enhances aggressiveness in prostate cancer. Using archival tissue samples, gain-of-function and loss-of-function studies, we show that PBK expression is up-regulated in prostate cancer, and its expression level is commensurate with invasiveness. Modulation of PBK expression and function causally regulates the invasive ability of prostate cancer cells. Production of matrix metalloproteinases-2 and -9, which are key players in metastatic invasion, is up-regulated, and the promoters of these genes are transcriptionally activated by PBK via increased β-catenin-TCF/LEF signaling. Prostate cancer tissue specimens show that PBK's expression correlates with aggressive disease and distant metastasis in bone, lymph node and abdomen. Our in vitro and in situ data are in agreement that PBK could be a prognostic biomarker for prostate cancer that would discriminate aggressive prostate cancer from indolent disease, and is a potential target for the therapeutic intervention of aggressive prostate cancer in men.
Highlights
Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in American men
We demonstrate that transcriptional activity of gene promoters of the matrix metalloproteinases (MMP) -2 and -9, which are overexpressed in aggressive carcinomas [25], is up-regulated in the presence of PDZ Domain-binding kinase (PBK)/T-LAK cell-originated protein kinase (TOPK), as a result of PBK-dependent activation of β-catenin-TCF/LEF signaling
Our data demonstrate that PBK/TOPK expression correlates with aggressiveness and invasive ability in this panel of prostate cell lines (Figure 1A and 1B), including the hormone responsive LNCaP and VCaP, hormonerefractory 22Rv1 and highly aggressively metastatic derivative PC-3M [27]
Summary
Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in American men. It is estimated that 1,000 men would have to be screened with the PSA test in order to prevent one death from prostate cancer, with a substantial degree of unnecessary treatment [3]. Prognostic nomograms, such as the D’Amicio risk stratification categories, which utilize a combination of stage, Gleason score from prostate biopsy and PSA level to predict the risk of recurrence and progression, do not possess sufficient accuracy to robustly predict www.impactjournals.com/oncotarget which neoplasias are likely to progress, or continue to be indolent [4]. There remains a strong need for the development of additional predictive markers that would be clinically useful in the treatment of prostate cancer patients [5]
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