In Vivo Activity of Insulin-Like Growth Factor Binding Protein-3 in Prevention of Prostate Cancer Progression
Abstract
Insulin-like growth factor (IGF) and IGF-binding protein-3 have been implicated in the growth and progression of prostate cancer. The effects of IGFBP-3 have been shown to mediated by both an inhibition of the actions of IGF on the type 1 receptor (IGF-IR) and through IGF-independent mechanisms. Although these effects have been demonstrated in prostate cancer cells in culture, there has been no in vivo demonstration in a relevant model of prostate cancer. Using the established mouse model of early prostate cancer (LPB-Tag or LADY) and two transgenic lines that overexpress IGFBP-3 or mutant IGFBP-3, we have tested the hypothesis that IGFBP-3 can inhibit or delay the progression of prostate cancer. We have established that tumor growth is reduced and progression delayed by both IGF-dependent and IGF-independent mechanisms. We have assessed the relative contributions of cell proliferation and apoptosis to tumor growth and demonstrated an early IGF-dependent effect on proliferation, and a later IGF-independent on cell survival. The pathways involved include PI-3 Kinase, pAKT and GSK3, and the ras/raf pathway for transcriptional activation. Our findings support further investigation of the potential of IGFBP-3 as a therapeutic agent in combination with inhibitors of IGF-1R.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2008
- Accession Number
- ADA519976
Entities
People
- Janice G. Dodd
Organizations
- University of Manitoba