You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2014MP24-16 ENHANCED SENSITIVITY TO SUNITINIB BY INHIBITION OF AKT1 EXPRESSION IN HUMAN CASTRATION-RESISTANT PROSTATE CANCER PC3 CELLS BOTH IN VITRO AND IN VIVO Masatomo Nishikawa, Hideaki Miyake, and Masato Fujisawa Masatomo NishikawaMasatomo Nishikawa More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , and Masato FujisawaMasato Fujisawa More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.297AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To date, Akt family has been shown to consist of three isoforms (Akt1, 2 and 3); however, of these, Akt1 is regarded as playing a central role in the regulation of malignant phenotype in various types of human malignancies, including prostate cancer. Despite being a widely accepted first-line agent against renal cell carcinoma, sunitinib has been demonstrated to have limited efficacies in several clinical trials targeting prostate cancer. The objective of this study was to investigate whether antitumor activity of sunitinib is enhanced by silencing Akt1 in a human castrarion-resistant prostate cancer (CRPC) PC3 model. METHODS We initially established PC3 in which the expression vector containing short hairpin RNA (shRNA) targeting Akt1 was introduced (PC3/sh-Akt1). Changes in various phenotypes of PC3/sh-Akt1 following treatment with sunitinib were compared to those of PC3 transfected with control vector alone (PC3/C) both in vitro and in vivo. RESULTS When cultured in the standard medium, in vitro growth of PC3/sh-Akt1 was almost similar to that of PC3/C. However, compared with PC3/C, PC3/sh-Akt1 showed a significantly higher sensitivity to sunitinib, accompanying downregulation of Bcl-2 and phosphorylated p44/42 mitogen-activated protein kinase as well as upregulation of BAX. In addition, treatment with sunitinib significantly suppressed the motility of PC3/sh-Akt1 compared with that of PC3/C. In vivo, administration of sunitinib induced the growth inhibition of both PC3/C and PC3/sh-Akt1; however, the growth inhibitory effect of sunitinib on PC3/sh-Akt1 tumor was more marked than that on PC3/C tumor. There were no significant differences in the Ki-67 expression and apoptotic index between PC3/C and PC3/sh-Akt1 tumors in mice receiving vehicle, whereas apoptotic index in PC3/ sh-Akt1 tumor in mice treated with sunitinib was significantly greater than that in PC3/C tumor, despite the lack of a significant difference in the Ki-67 expression between these two tumors even after treatment with sunitinib. CONCLUSIONS Growth inhibition of PC3 cells could not be achieved by inactivation of Akt1 signaling pathway alone; however, suppressed Akt1 activity appeared to significantly enhance the sensitivity of PC3 cells to sunitinib through the modulation of protein expression profiles associated with apoptotic and signal transduction pathways. Accordingly, combined treatment with Akt1 inhibitor and sunitinib could be a promising therapeutic approach for men with CRPC. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e265 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Masatomo Nishikawa More articles by this author Hideaki Miyake More articles by this author Masato Fujisawa More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...