Accession Number:

ADA519976

Title:

In Vivo Activity of Insulin-Like Growth Factor Binding Protein-3 in Prevention of Prostate Cancer Progression

Descriptive Note:

Final rept. 23 Sep 2004-22 Sep 2008

Corporate Author:

MANITOBA UNIV WINNIPEG DEPT OF MATHEMATICS

Personal Author(s):

• Dodd, Janice G.

Report Date:

2008-10-01

Pagination or Media Count:

31.0

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 rasraf 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.

Descriptors:

• *PROSTATE CANCER
• DEMONSTRATIONS
• NEOPLASMS
• THERAPY
• HYPOTHESES
• MICE
• TRANSCRIPTION(GENETICS)
• IN VIVO ANALYSIS
• CELLS(BIOLOGY)
• ANATOMICAL MODELS
• INSULIN
• GROWTH(PHYSIOLOGY)
• MODELS
• INHIBITION

Subject Categories:

• Anatomy and Physiology
• Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE