Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo.
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.
Burfeind
P
P
Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
Chernicky
C L
CL
Rininsland
F
F
Ilan
J
J
Ilan
J
J
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
D017931:DNA Primers; D016372:RNA, Antisense; D013431:Sulfates; D017967:Zinc Compounds; D019287:Zinc Sulfate; D008668:Metallothionein; D017526:Receptor, IGF Type 1