The insulin-like growth factor type I receptor stimulates growth and suppresses apoptosis in prostatic stromal cells.
Stromal cells derived from benign prostatic hyperplasia synthesize and secrete measurable levels of insulin-like growth factor (IGF). Seventy-two-hour conditioned medium obtained from these cells contains IGF-II at levels ranging from 125-177 ng/mL.10(6) cells. IGF-I is almost undetectable. RT-PCR analysis has demonstrated that the genes for both the type I IGF receptor (IGF-IR) and the type II IGF receptor (IGF-IIR) are expressed by benign stromal cells in vitro. Competition binding analysis for IGF-I and IGF-II confirmed the existence of binding sites for both ligands with respective Kd and binding capacities of 4.9 x 10(-9) mol/L and 6.6 x 10(5) sites/cell and 4.7 x 10(-9) mol/L and 3.8 x 10(6) sites/cell. Under serum-free conditions, IGF-I and IGF-II at 500 ng/mL induce 80% and 113% increases in stromal cell density, respectively, over a 96-h period. Incubation with the IGF-IR-neutralizing antibody alpha IR3 (50 micrograms/mL) reduces the rate of stromal cell proliferation by approximately 60-80% even in the presence of stimulatory concentrations of IGFs. Camptothecin-induced apoptosis is inhibited by the addition of IGF-I and -II (500 ng/mL). alpha IR3 suppresses these survival signals and itself induces cell death in the prostatic stroma. The data suggest that IGF-IR is a pivotal molecule in prostatic stromal cell maintenance, and that specific antagonism may offer a novel means of controlling the fibromuscular expansion characteristic of benign prostatic hyperplasia.
Grant
E S
ES
University Department of Surgery, University of Edinburgh, Western General Hospital, Scotland. esg@srv0.med.ed.ac.uk
Ross
M B
MB
Ballard
S
S
Naylor
A
A
Habib
F K
FK
D017209:Apoptosis / Q000502:physiology*; D002166:Camptothecin / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D053938:DNA Fragmentation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D011467:Prostate / Q000473:pathology*; D011470:Prostatic Hyperplasia / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology*
D017077:Culture Media, Conditioned; D017527:Receptor, IGF Type 2; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D002166:Camptothecin