MP37-13 ACCELERATED CELL PROLIFERATION AND ENHANCED RESISTANCE TO DOCETAXEL BY INHIBITION OF 4E-BINDING PROTEIN 1 EXPRESSION IN HUMAN CASTRATION-RESISTANT PROSTATE CANCER PC3 CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2015MP37-13 ACCELERATED CELL PROLIFERATION AND ENHANCED RESISTANCE TO DOCETAXEL BY INHIBITION OF 4E-BINDING PROTEIN 1 EXPRESSION IN HUMAN CASTRATION-RESISTANT PROSTATE CANCER PC3 CELLS Hiromoto Tei, Hideaki Miyake, and Masato Fujisawa Hiromoto TeiHiromoto Tei 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.2015.02.1276AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES 4E-binding protein 1 (4E-BP1) is an eukaryotic initiation factor 4E (eIF4E) binding protein that plays a critical role in the control of protein synthesis, cell growth and survival. When 4E-BP1 binds to eIF4E, this complex is shown to impede the cap-mediated translation, resulting in the induction of apoptotic cell death in a wide variety of cancer cells. The objective of this study was to clarify the functional significance of 4E-BP1 in the regulation of cell proliferation and sensitivity to proapoptotic stimuli in human castration-resistant prostate cancer (CRPC) PC3 cells. METHODS We initially established PC3, in which the expression vector containing short hairpin RNA (shRNA) targeting 4E-BP1, was introduced (PC3/sh-4E-BP1). Changes in the growth and sensitivity to docetaxel in PC3/sh-4E-BP1 were compared with those in PC3 transfected with control vector alone (PC3/C) both in vitro and in vivo. We also evaluated the expression of key molecules associated with apoptosis and signal transduction in PC3 sublines by Western blot analyses. RESULTS In vitro growth of PC3/sh-4E-BP1 was significantly faster than that in PC3/C. Expression levels of phosphorylated (p)-eIF4E, c-Myc, cyclin D1, p-Akt, p-p44-42 mitogen activated kinase (MAPK), p-mammalian target of rapamycin, p-S6K, Bcl-2, Bcl-xL and Mcl-1 in PC3/sh-4E-BP1 were significantly upregulated compared with those in PC3/C. Furthermore, PC3/sh-4E-BP1 showed a significantly higher sensitivity to docetaxel; that is, the IC50 of docetaxel in PC3/sh-4E-BP1 was approximately 10-times as high as that in PC3/C. Sensitivities of both PC3 sublines to docetaxel became similar by additional treatment with a specific inhibitor of c-Myc, Akt or MAPK. In vivo, the growth of PC3/sh-4E-BP1 tumors in nude mice was significantly faster than that of PC3/C tumors. Administration of docetaxel induced the growth inhibition of both PC3/C and PC3/sh-4E-BP1 tumors; however, the growth inhibitory effect of docetaxel on PC3/C tumors was more marked than that on PC3/sh-4E-BP1 tumors. CONCLUSIONS These findings suggest that 4E-BP1 plays an important role in the growth as well as resistance to proapoptotic therapeutic stimuli in CRPC cells through the regulation of major molecules mediating the signal transduction and apoptosis. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e442-e443 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiromoto Tei 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 ...