title: Both IGF1R and INSR Knockdown Exert Antitumorigenic Effects in Prostate Cancer In Vitro and In Vivo.
abstract: The IGF network with its main receptors IGF receptor 1 (IGF1R) and insulin receptor (INSR) is of major importance for cancer initiation and progression. To date, clinical studies targeting this network were disappointing and call for thorough analysis of the IGF network in cancer models. We highlight the oncogenic effects controlled by IGF1R and INSR in prostate cancer cells and show similarities as well as differences after receptor knockdown (KD). In PC3 prostate cancer cells stably transduced with inducible short hairpin RNAs, targeting IGF1R or INSR attenuated cell growth and proliferation ultimately driving cells into apoptosis. IGF1R KD triggered rapid and strong antiproliferative and proapoptotic responses, whereas these effects were less pronounced and delayed after INSR KD. Down-regulation of the antiapoptotic proteins myeloid cell leukemia-1 and survivin was observed in both KDs, whereas IGF1R KD also attenuated expression of prosurvival proteins B cell lymphoma-2 and B cell lymphoma-xL. Receptor KD induced cell death involved autophagy in particular upon IGF1R KD; however, no difference in mitochondrial energy metabolism was observed. In a mouse xenograft model, induction of IGF1R or INSR KD after tumor establishment eradicated most of the tumors. After 20 days of receptor KD, tumor cells were found only in 1/14 IGF1R and 3/14 INSR KD tumor remnants. Collectively, our data underline the oncogenic functions of IGF1R and INSR in prostate cancer namely growth, proliferation, and survival in vitro as well as in vivo and identify myeloid cell leukemia-1 and survivin as important mediators of inhibitory and apoptotic effects.
authors.affiliation: Division of Experimental Urology (P.O., I.H., I.E.E., H.K., P.M.), Department of Urology, Medical University, 6020 Innsbruck, Austria; Division of Genetic Epidemiology (B.S.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University, 6020 Innsbruck, Austria; Department of Internal Medicine IV (N.H.), Medical University, 6020 Innsbruck, Austria; and Division of Molecular Pathophysiology (S.G.), Biocenter, Medical University, 6020 Innsbruck, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ofer
authors.affiliation: Division of Experimental Urology (P.O., I.H., I.E.E., H.K., P.M.), Department of Urology, Medical University, 6020 Innsbruck, Austria; Division of Genetic Epidemiology (B.S.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University, 6020 Innsbruck, Austria; Department of Internal Medicine IV (N.H.), Medical University, 6020 Innsbruck, Austria; and Division of Molecular Pathophysiology (S.G.), Biocenter, Medical University, 6020 Innsbruck, Austria.
authors.forename: Isabel
authors.initials: I
authors.lastname: Heidegger
authors.affiliation: Division of Experimental Urology (P.O., I.H., I.E.E., H.K., P.M.), Department of Urology, Medical University, 6020 Innsbruck, Austria; Division of Genetic Epidemiology (B.S.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University, 6020 Innsbruck, Austria; Department of Internal Medicine IV (N.H.), Medical University, 6020 Innsbruck, Austria; and Division of Molecular Pathophysiology (S.G.), Biocenter, Medical University, 6020 Innsbruck, Austria.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Eder
authors.affiliation: Division of Experimental Urology (P.O., I.H., I.E.E., H.K., P.M.), Department of Urology, Medical University, 6020 Innsbruck, Austria; Division of Genetic Epidemiology (B.S.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University, 6020 Innsbruck, Austria; Department of Internal Medicine IV (N.H.), Medical University, 6020 Innsbruck, Austria; and Division of Molecular Pathophysiology (S.G.), Biocenter, Medical University, 6020 Innsbruck, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schöpf
authors.affiliation: Division of Experimental Urology (P.O., I.H., I.E.E., H.K., P.M.), Department of Urology, Medical University, 6020 Innsbruck, Austria; Division of Genetic Epidemiology (B.S.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University, 6020 Innsbruck, Austria; Department of Internal Medicine IV (N.H.), Medical University, 6020 Innsbruck, Austria; and Division of Molecular Pathophysiology (S.G.), Biocenter, Medical University, 6020 Innsbruck, Austria.
authors.forename: Hannes
authors.initials: H
authors.lastname: Neuwirt
authors.affiliation: Division of Experimental Urology (P.O., I.H., I.E.E., H.K., P.M.), Department of Urology, Medical University, 6020 Innsbruck, Austria; Division of Genetic Epidemiology (B.S.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University, 6020 Innsbruck, Austria; Department of Internal Medicine IV (N.H.), Medical University, 6020 Innsbruck, Austria; and Division of Molecular Pathophysiology (S.G.), Biocenter, Medical University, 6020 Innsbruck, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Geley
authors.affiliation: Division of Experimental Urology (P.O., I.H., I.E.E., H.K., P.M.), Department of Urology, Medical University, 6020 Innsbruck, Austria; Division of Genetic Epidemiology (B.S.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University, 6020 Innsbruck, Austria; Department of Internal Medicine IV (N.H.), Medical University, 6020 Innsbruck, Austria; and Division of Molecular Pathophysiology (S.G.), Biocenter, Medical University, 6020 Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.affiliation: Division of Experimental Urology (P.O., I.H., I.E.E., H.K., P.M.), Department of Urology, Medical University, 6020 Innsbruck, Austria; Division of Genetic Epidemiology (B.S.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University, 6020 Innsbruck, Austria; Department of Internal Medicine IV (N.H.), Medical University, 6020 Innsbruck, Austria; and Division of Molecular Pathophysiology (S.G.), Biocenter, Medical University, 6020 Innsbruck, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Massoner
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D034741:RNA, Small Interfering; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin