Overexpression of insulin-like growth factor binding protein-5 helps accelerate progression to androgen-independence in the human prostate LNCaP tumor model through activation of phosphatidylinositol 3'-kinase pathway

Endocrinology. 2000 Jun;141(6):2257-65. doi: 10.1210/endo.141.6.7520.


Although insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) is highly up-regulated in normal and malignant prostate tissues after androgen withdrawal, its functional role in castration-induced apoptosis and androgen-independent progression remains undefined. To analyze the functional significance of IGFBP-5 overexpression in IGF-I-mediated mitogenesis and progression to androgen-independence, IGFBP-5-overexpressing human androgen-dependent LNCaP prostate cancer cells were generated by stable transfection. The growth rates of IGFBP-5-transfected LNCaP cells were significantly faster, compared with either the parental or vector-only transfected LNCaP cells in both the presence and absence ofdihydrotestosterone. IGFBP-5-induced increases in LNCaP cell proliferation occurs through both IGF-I-dependent and -independent pathways, with corresponding increases in the cyclin D1 messenger RNA expression and the fraction of cells in S + G2/M phases of the cell cycle. Changes in Akt/protein kinase B, a downstream component of phosphatidylinositol 3'-kinase (PI3K) pathway, in the LNCaP sublines also paralleled changes in their growth rates. Although treatment with a PI3K inhibitor induced apoptosis in both control and IGFBP-5-overexpressing LNCaP cells, this PI3K inhibitor-induced apoptosis was prevented by exogenous IGF-I treatment only in IGFBP-5 transfectants, suggesting that IGFBP-5 overexpression can potentiate the antiapoptotic effects of IGF-I. Furthermore, tumor growth and serum prostate-specific antigen levels increased several fold faster in mice bearing IGFBP-5-transfected LNCaP tumors after castration, despite having similar tumor incidence and tumor growth rates with controls when grown in intact mice before castration. Collectively, these data suggest that IGFBP-5 overexpression in prostate cancer cells after castration is an adaptive cell survival mechanism that helps potentiate the antiapoptotic and mitogenic effects of IGF-I, thereby accelerating progression to androgen independence through activation of the PI3K-Akt/ protein kinase B signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / pharmacology*
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • Cyclin D1 / genetics
  • Dihydrotestosterone / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Gene Expression*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5 / genetics
  • Insulin-Like Growth Factor Binding Protein 5 / physiology*
  • Insulin-Like Growth Factor I / pharmacology
  • Male
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • RNA, Messenger / metabolism
  • Transfection
  • Tumor Cells, Cultured


  • Androgens
  • Enzyme Inhibitors
  • Insulin-Like Growth Factor Binding Protein 5
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Messenger
  • Dihydrotestosterone
  • Cyclin D1
  • Insulin-Like Growth Factor I
  • Mitogen-Activated Protein Kinases
  • Prostate-Specific Antigen