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Submitted on October 6, 2005
Accepted on February 2, 2006
Departments of Physiology and Internal Medicine, University of Manitoba, Winnipeg, Canada
IGFBP-3 inhibits cell growth and promotes apoptosis by sequestering free IGFs. In addition IGFBP-3 has IGF-independent, pro-apoptotic, anti-proliferative effects on prostate cancer cells in vitro. Expression of the large T-antigen (Tag) under the probasin promoter in LPB-Tag mice results in prostate tumorigenesis. To investigate the IGF-dependent and IGF-independent effects of IGFBP-3 on prostate tumor growth we crossed LPB-Tag mice with CMVBP-3 and PGKBP-3 mice which overexpress IGFBP-3 under the cytomegalovirus promoter and the phosphoglycerate kinase promoter respectively, and also PGKmBP-3 mice that express I56G/L80G/L81G-IGFBP-3, a mutant, that does not bind IGF-I but retains IGF-independent pro-apoptotic effects in vitro. Prostate tumor size and the steady-state level of p53 were attenuated in LPB-Tag/CMVBP-3 and LPB-Tag/PGKBP-3 mice compared with LPB-Tag/Wt mice. A more marked effect was observed in LPB-Tag/CMVBP-3 compared with LPB-Tag/PGKBP-3 reflecting increased levels of transgene expression in CMVBP-3 prostate tissue. No attenuation of tumor growth was observed in LPB-Tag/PGKmBP-3 mice during the early tumor development indicating that the inhibitory effects of IGFBP-3 were most likely IGF-dependent during the initiation of tumorigenesis. At 15 weeks of age EGF receptor expression was increased in LPB-Tag/Wt and LPB-Tag/PGKmBP-3 tissue compared with LPB-Tag/PGKBP-3. IGF-receptor was increased in all transgenic mice but pAkt expression, a marker of downstream IGF-I action, was increased only in LPB-Tag/Wt and LPB-Tag/PGKmBP-3. After 15 weeks of age a marked reduction in tumor growth was apparent in LPB-Tag/PGKmBP-3 mice indicating that the IGF-independent effects of IGFBP-3 may be important in inhibiting tumor progression.
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