735 THE IMPACT OF INSULIN AND ITS RECEPTORS ON IGF TARGETING THERAPIES IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011735 THE IMPACT OF INSULIN AND ITS RECEPTORS ON IGF TARGETING THERAPIES IN PROSTATE CANCER Isabel Heidegger, Petra Massoner, and Helmut Klocker Isabel HeideggerIsabel Heidegger Innsbruck, Austria More articles by this author , Petra MassonerPetra Massoner Innsbruck, Austria More articles by this author , and Helmut KlockerHelmut Klocker Innsbruck, Austria More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1704AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES With over 60 ongoing clinical trials the insulin-like growth factor (IGF) signaling pathway represents one of the most promising targets in the development of anti-cancer therapeutics. Not all patients benefit from therapies targeting the IGF pathway, but there are no defined criteria to predict a response. In clinical studies hyperglycemia has been reported as the most common side effect, a mechanism connected to the insulin receptor(INSR) pathway. The IGF axis is a complex network interacting with INSRs. The INSR itself appears in two isoforms (INSR-A and INSR-B) one of which (INSR-A) plays a role in cancer development and progression. INSRs and IGF1R are closely related and form hybride receptors. Nevertheless, only a few studies addressed the molecular connections between insulin and cancer. METHODS We analyzed the expression of INSRs in different prostate cancer cell models on protein- (WB) and mRNA level (rtPCR). To investigate the function of the INSRs overexpression- (plasmids) and downregulation (siRNA) experiments were performed. Cell proliferation was measured by 3H-thymidine incorporation assays and determination of cell numbers; migration was assessed by wound healing assay; and colony formation using a clonogenic assay. Apoptosis was measured by western blot, FACS analysis (PI staining) and a 3/7 caspase activity assay. Cell glucose levels were measured using the Gluc Cell Monitoring System™. RESULTS Different cell lines expressed different ratios of INSR isoforms. IGF1R and INSR-A overexpression significantly increased cell proliferation, whereas the INSR-B did not affect proliferation. Alike migration and colony formation of cancer cells was increased upon IGF1R and INSR-A overexpression. IGF1R and INSR-A overexpression, did not protect cells from drug induced apoptosis. Interestingly, overexpression or downegulation of IGF1R also influenced INSR mRNA and protein levels suggesting a mutual modulation of each other. Overexpression of INSRs decreased and overexpression of INSR increased the glucose levels of cancer cells significantly. CONCLUSIONS The IGF axis is a complex interacting network interfering with INSRs. Based on these results we assume that especially the INSR-A should also be targeted to improve therapeutic outcomes of anti IGF cancer treatment. Our results suggest a negative feedback mechanism as a possible explanation for the observed hyperglycemia in patients treated with IGF targeting therapies. This could be the first step toward a successful handling of this most common side effect of IGF targeting therapies. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e295 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Isabel Heidegger Innsbruck, Austria More articles by this author Petra Massoner Innsbruck, Austria More articles by this author Helmut Klocker Innsbruck, Austria More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...