420 IN VIVO CASTRATION-RESISTANT ACCELERATION OF PROSTATE CANCER INHIBITED BY A SMALL MOLECULE INHIBITOR OF INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR/INSULIN RECEPTOR TYROSINE KINASE

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011420 IN VIVO CASTRATION-RESISTANT ACCELERATION OF PROSTATE CANCER INHIBITED BY A SMALL MOLECULE INHIBITOR OF INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR/INSULIN RECEPTOR TYROSINE KINASE Takamitsu Inoue, Mahvash Zakikhani, Matei Mireuta, Marie-José Blouin, and Michael Pollak Takamitsu InoueTakamitsu Inoue Akita, Japan More articles by this author , Mahvash ZakikhaniMahvash Zakikhani Montreal, Canada More articles by this author , Matei MireutaMatei Mireuta Montreal, Canada More articles by this author , Marie-José BlouinMarie-José Blouin Montreal, Canada More articles by this author , and Michael PollakMichael Pollak Montreal, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.509AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Increased serum insulin level has been reported to be associated with increased risk of prostate cancer diagnosis and recurrence. It is plausible that insulin signaling could influence prostate cancer evolution to castration resistant prostate cancer (CRPC). We investigated the in vivo inhibitory effect on androgen independent acceleration of LNCaP xenograft using small molecule inhibitor of insulin-like growth factor 1 receptor/insulin receptor tyrosine kinase in order to analyze the contribution of insulin signaling on the development of CRPC. METHODS A total of 2 × 10 6 LNCaP cells were injected subcutaneously in right flank of the Balb/c nu/nu mice. When tumor volume was reached 200 mm3, mice were randomized to castrated group or non-castrated group and compared the tumor volume. When tumor volume was reached approximately 500 mm3, mice were randomized to inhibitor-treated group and non-treated group in each castrated and non-castrated group mice. Western blot analyses and RT-PCR were performed using the tumor tissue obtained at euthanasia. RESULTS In the short term, the tumor volume was significantly decreased in the castrated group compared with the non-castrated group (p = 0.013); however, in the long term, the tumor volume was significantly increased in the castrated group compared to the non-castrated group (p < 0.0001). In the castrated group, the tumor volume was significantly decreased by inhibitor treatment (p = 0.023) while there was no effect in the non-castrated group (p = 0.49). Western blot analyses using tumor lysate demonstrated that total IR expression was increased in castrated mice compared to non-castrated (p = 0.02), while total IGF-1R was decreased (p = 0.02). Phosphorylation of IR, which was augmentable by insulin injection, was inhibited by tyrosine kinase inhibitor. CONCLUSIONS This experiment suggests that insulin signaling may be one of the pathways involved in progression of prostate cancer to castration resistance. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e169 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takamitsu Inoue Akita, Japan More articles by this author Mahvash Zakikhani Montreal, Canada More articles by this author Matei Mireuta Montreal, Canada More articles by this author Marie-José Blouin Montreal, Canada More articles by this author Michael Pollak Montreal, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...