965 LONG-TERM ANDROGEN ABLATION AND TREATMENT WITH TAXANES UP-REGULATE PHOSPHORYLATED AKT IN CASTRATION RESISTANT PROSTATE CANCER

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You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2012965 LONG-TERM ANDROGEN ABLATION AND TREATMENT WITH TAXANES UP-REGULATE PHOSPHORYLATED AKT IN CASTRATION RESISTANT PROSTATE CANCER Takeo Kosaka, Akira Miyajima, Suguru Shirotake, Eiji Kikuchi, and Mototsugu Oya Takeo KosakaTakeo Kosaka Tokyo, Japan More articles by this author , Akira MiyajimaAkira Miyajima Tokyo, Japan More articles by this author , Suguru ShirotakeSuguru Shirotake Tokyo, Japan More articles by this author , Eiji KikuchiEiji Kikuchi Tokyo, Japan More articles by this author , and Mototsugu OyaMototsugu Oya Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1064AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES There are still few effective therapeutic options for advanced prostate cancer. It remains unknown how sensitivity to taxanes changes during progression to more aggressive castration resistant prostate cancer under androgen ablation. The aim of this study was to elucidate the change of the sensitivity to docetaxel during CRPC progression, especially focusing on the change of phosphorylated Akt (pAkt) status. METHODS Two human CRPC cell lines (C4-2, C4-2AT6) were used in this study. C4-2AT6 cells were established under androgen ablation for six months. We investigated sensitivity to docetaxel in C4-2 and C4-2AT6 cells in vitro and in vivo. Phosphorylated Akt status was To assess whether docetaxel sensitivity was associated with castration resistance, PI3K/Akt signaling pathways were inhibited by using a PI3K/Akt inhibitor:LY294002. RESULTS C4-2 and C4-2AT6 cells were treated with increasing concentrations of docetaxel in vitro. C4-2AT6 cells showed more resistance to docetaxel than C4-2 cells in vitro. To investigate the sensitivity of C4-2 and C4-2AT6 tumors to docetaxel in vivo we assigned castrated nude mice to 3 groups, including control, docetaxel (4 mg/kg) and docetaxel (8 mg/kg). In C4-2 tumors docetaxel treatment led to a dramatic, dose dependent decrease in tumor volume compared with that in controls. On the other hand, in C4-2AT6 tumors docetaxel led to a slight decrease in tumor volume compared with that in controls. Results indicate that C4-2AT6 cells acquired resistance to docetaxel under the androgen ablation condition in vivo as well as in vitro. We investigated the expression and status of tAkt and pAkt in C4-2 and C4-2AT6 cells. Western blot analysis showed that C4-2AT6 cells showed significantly higher pAkt expression than C4-2 cells. We evaluated tAkt and pAkt expression by immunohistochemistry according to semiquantified scoring methods in a mouse xenograft mode. The pAkt expression score in C4-2AT6 tumors was significantly higher than in C4-2 tumors (p<0.01). Results indicate that pAkt was significantly induced by docetaxel treatment in C4-2AT6 tumors. After treatment with docetaxel and LY294002, C4-2AT6 cells showed a marked increase in sensitivity to docetaxel, accompanied by enhanced apoptosis. Results indicate that increased pAkt activity explains the resistance of C4-2AT6 cells to docetaxel. CONCLUSIONS These findings demonstrated the up-regulation of pAkt under androgen ablation and that its further activation by docetaxel accounts for the resistance to decetaxel and progression into CRPC. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e393 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takeo Kosaka Tokyo, Japan More articles by this author Akira Miyajima Tokyo, Japan More articles by this author Suguru Shirotake Tokyo, Japan More articles by this author Eiji Kikuchi Tokyo, Japan More articles by this author Mototsugu Oya Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...