Mp98-17 targeting protein kinase d2 may represent a therapeutic strategy for bladder cancer

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology V1 Apr 2017MP98-17 TARGETING PROTEIN KINASE D2 MAY REPRESENT A THERAPEUTIC STRATEGY FOR BLADDER CANCER Mohammad siddiqui, Iawen Hsu, Quentin Li, Thomas Sanford, Reema Railkar, and Piyush Agarwal Mohammad siddiquiMohammad siddiqui More articles by this author , Iawen HsuIawen Hsu More articles by this author , Quentin LiQuentin Li More articles by this author , Thomas SanfordThomas Sanford More articles by this author , Reema RailkarReema Railkar More articles by this author , and Piyush AgarwalPiyush Agarwal More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3082AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Protein Kinase D (PKD) is downstream of protein kinase C and it can regulate cell survival, proliferation, invasion, and migration. It has been implicated in several cancers and exists in three major isoforms. We sought to investigate the role of PKD2 in bladder cancer. METHODS PKD2 protein expression was assessed using Oncomine data for normal urothelium and bladder tumors. Several bladder cancer cell lines (T24, T24T, UMUC1, and TCCSUP) were assessed for cell proliferation, growth in low attachment agar (GILA), invasion, and migration with and without stable knock-down of PKD2. The UMUC1 cell line was evaluated in xenografts for tumor growth with and without stable knock-down of PKD2. A flank xenograft experiment was performed with oral gavage in mice using CRT0066101, a pan-PKD inhibitor. Western blot analysis was used to confirm silencing and evaluate downstream targets of PKD2. RESULTS Oncomine data confirmed increased mRNA expression of PKD2 in bladder tumors compared with normal urothelium. Selective knock-down of PKD2 in the cell lines inhibited cell proliferation, GILA colony formation, invasion, and migration. UMUC1 cells with silenced PKD2 failed to grow tumors in xenografts. Tumor xenografts treated with CRT0066101 had significant tumor growth inhibition compared to tumor controls (p<0.0001). Loss of phosphorylated c-Jun, a key mediator of cell proliferation and apoptosis, is noted with PKD2 silencing and PKD pharmacologic inhibition. CONCLUSIONS PKD2 is overexpressed in bladder tumors and inhibition of PKD2 either through selective silencing of PKD2 or the use of a pan-PKD inhibitor results in tumor growth inhibition in cell lines and xenografts. Targeting PKD2 results in loss of active c-Jun and may represent a therapeutic strategy in urothelial cancer. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1318 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Mohammad siddiqui More articles by this author Iawen Hsu More articles by this author Quentin Li More articles by this author Thomas Sanford More articles by this author Reema Railkar More articles by this author Piyush Agarwal More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...