Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice.
BACKGROUND
The mechanisms by which castration induces prostate involution are largely unknown.


METHODS
Early responses to castration in mouse ventral prostate (VP) were explored by quantitative microscopy, cDNA array expression, quantitative RT-PCR, and Western blot analysis. As several changes occurred in the insulin-like growth factor (IGF) system this was studied in more detail. Laser micro-dissection was used to localize sites of IGF-1 and IGF-1 receptor (IGF-R1) production. IGF-1 protein levels and IGF-R1 mediated signaling via insulin regulated substrate 1 and 2 (IRS-1 and 2) were examined. IGF-1 was injected into the VP in intact, and castrated mice and effects studied 1 day later.


RESULTS
IGF-1 and IGF binding protein 2 (IGFBP-2) mRNA were rapidly reduced whereas IGFBP-3 and IGF-R1 mRNA were increased after castration. IGF-1 was principally produced in the stromal compartment, while IGF-R1 was produced in both epithelial and stromal cells. IGF-1 and IRS-1 protein levels were decreased 1 and 3 days after castration, respectively, while IRS-2 was unchanged. Inactivating phosphorylation of IRS-1 at serine 307 was increased 1 day after castration, and activating phosphorylation at tyrosine 612 was decreased 2 days later. These changes were accompanied by decreased cell proliferation and increased cell death in the glandular and vascular compartment. Local injection of IGF-1 increased vascular density and epithelial cell proliferation in intact mice, but had no effect in castrated animals.


CONCLUSIONS
Decreased IGF-1 levels and action may mediate some of the key features of castration-induced prostate involution.
Ohlson
Nina
N
Department of Medical Biosciences, Umeå University, Sweden. nina.ohlson@medbio.umu.se
Bergh
Anders
A
Persson
Malin Lindhagen
ML
Wikström
Pernilla
P
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D010750:Phosphoproteins / Q000378:metabolism; D011467:Prostate / Q000098:blood supply / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism
D055504:Insulin Receptor Substrate Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I