MP52-20 POST-TRANSLATIONAL MODIFICATION MEDIATED BY THE PROLYL ISOMERASE PIN1 ACCERELATE CANCER PROGRESSION IN CASTRATION RESISTANT PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2014MP52-20 POST-TRANSLATIONAL MODIFICATION MEDIATED BY THE PROLYL ISOMERASE PIN1 ACCERELATE CANCER PROGRESSION IN CASTRATION RESISTANT PROSTATE CANCER Yota Yasumizu, Takeo Kosaka, Yasumasa Miyazaki, Eiji Kikuchi, Akira Miyajima, and Mototsugu Oya Yota YasumizuYota Yasumizu More articles by this author , Takeo KosakaTakeo Kosaka More articles by this author , Yasumasa MiyazakiYasumasa Miyazaki More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , Akira MiyajimaAkira Miyajima More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1630AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives The prolyl isomerase Pin1 regulates phosphorylated status of proteins by catalyzing the cis-trans isomerization of phosphorylated Ser/Thr and Pro motifs, and plays an important role in cancer progression. The aim of this study was to establish a new treatment strategy for docetaxel resistant CRPC with a special focus on inhibition of Pin1. Methods Human CRPC cell lines: C4-2 and C4-2AT6 cell lines were used in this study. The C4-2AT6 cell line was established from C4-2 cells grown in androgen ablated serum for six months. The efficacy of Pin1 inhibitor: juglone was examined in CRPC cell lines. Human untreated prostate cancer tissues were obtained during radical prostatectomy at Keio University Hospital. Results We compared the cytotoxic effect of docetaxel (DTX) on C4-2 and C4-2AT6 cells by cell viability assay. In C4-2 and C4-2AT6 cells, the relative cell viability treated with 5nM DTX was 38.0% ± 5.2% and 59.1% ± 6.3%, respectively. These results indicated that C4-2AT6 cells showed significantly higher resistance to DTX than C4-2 cells. Next we evaluated the cytotoxic effect of juglone on C4-2AT6. The relative cell viability was 51.2 ± 3.2% with 30µM Juglone and 34.9 ± 3.8% with combined 5nM DTX and 30µM Juglone. Juglone significantly inhibited cell proliferation of C4-2AT6. When combined with DTX, Juglone showed significantly higher cytotoxicity than monotherapy (p<0.05). We previously demonstrated the efficacy of dual PI3K/mTOR inhibitor: NVP-BEZ235 against C4-2AT6. Pin1 regulates phosphorylated status of PI3K/Akt/mTOR pathway. Therefore, we examined the synergic effect of Juglone and NVP-BEZ235. The relative cell viability treated with 300nM NVP-BEZ235 was 49.3 ± 3.2% and 43.0 ± 3.8% with combined 300nM NVP-BEZ235 and 30µM Juglone. The combination of Juglone and NVP-BEZ235 shows little synergic effect on C4-2AT6 cells. In vivo, we examined a mouse xenogrftmodel of C4-2AT6 cells treated with DTX (2mg/kg) or NVP-BEZ235 (12.5mg/kg/day). In immunohistochemistry, tumors treated with DTX showed up-regulation of Pin1, while tumors treated with NVP-BEZ235 showed little expression of Pin1. These results suggest that Pin1 inhibitor shows the significant effect on tumors with up-regulation of Pin1. We confirmed the expression of Pin1 in human samples by immunohistochemistry. Specimens with a high Gleason score (>8) and a high pathological classification (pT3) showed significantly elevated Pin1 expression (p>0.05). Conclusions The combination of Juglone and DTX showed significant anti-tumor effects in CRPC. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e587 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Yota Yasumizu More articles by this author Takeo Kosaka More articles by this author Yasumasa Miyazaki More articles by this author Eiji Kikuchi More articles by this author Akira Miyajima More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...