PBK/TOPK enhances aggressive phenotype in prostate cancer via β-catenin-TCF/LEF-mediated matrix metalloproteinases production and invasion

// Joshua D. Brown-Clay 1 , Deepika N. Shenoy 1 , Olga Timofeeva 2 , Bhaskar V. Kallakury 3 , Asit K. Nandi 4 and Partha P. Banerjee 1 1 Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA 2 Departments of Oncology and Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 3 Department of Pathology, Georgetown University Medical Center, Washington, DC, USA 4 Current address: Cockeysville, Maryland Correspondence to: Partha P. Banerjee, email: // Keywords : PBK/TOPK, prostate cancer, metastasis, cell invasion Received : January 14, 2015 Accepted : March 11, 2015 Published : March 30, 2015 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 i n 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.