Insulin-like growth factor (IGF) binding protein-3 attenuates prostate tumor growth by IGF-dependent and IGF-independent mechanisms.
IGF binding protein (IGFBP)-3 inhibits cell growth and promotes apoptosis by sequestering free IGFs. In addition IGFBP-3 has IGF-independent, proapoptotic, antiproliferative effects on prostate cancer cells in vitro. Expression of the large T-antigen (Tag) under the long probasin promoter (LPB) 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 cytomegalovirus (CMVBP-3) and phosphoglycerate kinase (PGKBP-3) mice that overexpress IGFBP-3 under the cytomegalovirus promoter and the phosphoglycerate kinase promoter, respectively, and also I56G/L80G/L81G-mutant IGFBP-3 (PGKmBP-3) mice that express I56G/L80G/L81G-IGFBP-3, a mutant, that does not bind IGF-I but retains IGF-independent proapoptotic 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/wild-type (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 wk of age, epidermal growth factor 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 wk 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.
Department of Physiology, University of Manitoba, Winnipeg, Canada.
Josef V
JV
Silha
Patricia C
PC
Sheppard
Suresh
S
Mishra
Yaoting
Y
Gui
Jacquie
J
Schwartz
Janice G
JG
Dodd
Liam J
LJ
Murphy
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003433:Crosses, Genetic; D003587:Cytomegalovirus / Q000378:metabolism; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D015151:Immunoblotting; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism* / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D010735:Phosphoglycerate Kinase / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012044:Regression Analysis; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes; D015854:Up-Regulation
D018972:Insulin-Like Growth Factor Binding Protein 3; D008024:Ligands; D012333:RNA, Messenger; D012313:RNA; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D010735:Phosphoglycerate Kinase; D012260:Ribonucleases