Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice

Prostate. 2006 Dec 1;66(16):1687-97. doi: 10.1002/pros.20368.

Abstract

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.

Conclusion: Decreased IGF-1 levels and action may mediate some of the key features of castration-induced prostate involution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / physiology
  • Epithelial Cells / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor Binding Protein 2 / biosynthesis
  • Insulin-Like Growth Factor Binding Protein 2 / genetics
  • Insulin-Like Growth Factor Binding Protein 2 / metabolism
  • Insulin-Like Growth Factor Binding Protein 3 / biosynthesis
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism
  • Insulin-Like Growth Factor I / biosynthesis
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor I / pharmacology
  • Male
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Orchiectomy*
  • Phosphoproteins / metabolism
  • Prostate / blood supply
  • Prostate / cytology
  • Prostate / drug effects
  • Prostate / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Stromal Cells / metabolism

Substances

  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor Binding Protein 2
  • Insulin-Like Growth Factor Binding Protein 3
  • Irs1 protein, mouse
  • Phosphoproteins
  • RNA, Messenger
  • Insulin-Like Growth Factor I