title: Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo.
abstract: Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissue-type plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Subcutaneous injection of either nontransfected PA-III or PA-III cells transfected with vector minus the IGF-IR insert into nude mice resulted in large tumors after 4 weeks. However, mice injected with IGF-IR antisense-transfected PA-III cells either developed tumors 90% smaller than controls or remained tumor-free after 60 days of observation. When control-transfected PA-III cells were inoculated over the abraded calvaria of nude mice, large tumors formed with invasion of tumor cells into the brain parenchyma. In contrast, IGF-IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targeting IGF-IR as a potential treatment for prostate cancer.
authors.affiliation: Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: P
authors.initials: P
authors.lastname: Burfeind
authors.forename: C L
authors.initials: CL
authors.lastname: Chernicky
authors.forename: F
authors.initials: F
authors.lastname: Rininsland
authors.forename: J
authors.initials: J
authors.lastname: Ilan
authors.forename: J
authors.initials: J
authors.lastname: Ilan
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology* / Q000628:therapy; D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D017931:DNA Primers; D015870:Gene Expression; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy; D016372:RNA, Antisense / Q000494:pharmacology*; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015183:Restriction Mapping; D013431:Sulfates / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D017967:Zinc Compounds / Q000494:pharmacology; D019287:Zinc Sulfate
chemical_list: D017931:DNA Primers; D016372:RNA, Antisense; D013431:Sulfates; D017967:Zinc Compounds; D019287:Zinc Sulfate; D008668:Metallothionein; D017526:Receptor, IGF Type 1