Review

Signalling pathways involved in antiproliferative effects of IGFBP-3: a review

R C Baxter

Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW 2065, Australia

Correspondence to:
Dr Baxter robaxter{at}med.usyd.edu.au

Insulin-like growth factor binding protein-3 (IGFBP-3), the major circulating carrier protein for IGFs, is also active in the cellular environment as a potent antiproliferative agent. It appears to function both by cell cycle blockade and the induction of apoptosis. Transfection of p53 negative T47D breast cancer cells to express IGFBP-3 leads to induction of the apoptotic protein bax and an increase in sensitivity to ionising radiation. IGFBP-3 can be transported to the nucleus by an importin ß mediated mechanism, where it has been shown to interact with the retinoid X receptor and possibly other nuclear elements. Expression of oncogenic ras is associated with resistance to exogenous IGFBP-3, the effect being reversible by inhibition of mitogen activated protein (MAP) kinase phosphorylation. IGFBP-3 antiproliferative signalling appears to require an active transforming growth factor ß (TGF-ß) signalling pathway, and IGFBP-3 stimulates phosphorylation of the TGF-ß signalling intermediates Smad2 and Smad3. These recent findings all point to a complex intracellular mode of action of IGFBP-3, which will need to be better understood if anti-cancer treatments are to take advantage of the antiproliferative activity of IGFBP-3.

Key Words: insulin-like growth factor binding protein-3 • signalling pathway • apoptosis • transforming growth factor ß

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Lue, Y., Wang, C., Cui, Y., Wang, X., Sha, J., Zhou, Z., Xu, J., Wang, C., Sinha Hikim, A. P., Swerdloff, R. S. (2009). Levonorgestrel Enhances Spermatogenesis Suppression by Testosterone with Greater Alteration in Testicular Gene Expression in Men. Biol. Reprod. 80: 484-492 [Abstract] [Full Text]  
• Diorio, C., Brisson, J., Berube, S., Pollak, M. (2008). Genetic Polymorphisms Involved in Insulin-like Growth Factor (IGF) Pathway in Relation to Mammographic Breast Density and IGF Levels. Cancer Epidemiol. Biomarkers Prev. 17: 880-888 [Abstract] [Full Text]  
• Gray, J., Mao, J. T., Szabo, E., Kelley, M., Kurie, J., Bepler, G. (2007). Lung Cancer Chemoprevention: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition). Chest 132: 56S-68S [Abstract] [Full Text]  
• Chen, C., Freeman, R., Voigt, L. F., Fitzpatrick, A., Plymate, S. R., Weiss, N. S. (2006). Prostate Cancer Risk in Relation to Selected Genetic Polymorphisms in Insulin-like Growth Factor-I, Insulin-like Growth Factor Binding Protein-3, and Insulin-like Growth Factor-I Receptor. Cancer Epidemiol. Biomarkers Prev. 15: 2461-2466 [Abstract] [Full Text]  
• McCarty, M. F., Block, K. I. (2006). Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy. Integr Cancer Ther 5: 252-268 [Abstract]  
• Wang, Z., Chakravarty, G., Kim, S., Yazici, Y. D., Younes, M. N., Jasser, S. A., Santillan, A. A., Bucana, C. D., El-Naggar, A. K., Myers, J. N. (2006). Growth-Inhibitory Effects of Human Anti-Insulin-Like Growth Factor-I Receptor Antibody (A12) in an Orthotopic Nude Mouse Model of Anaplastic Thyroid Carcinoma. Clin. Cancer Res. 12: 4755-4765 [Abstract] [Full Text]  
• Burrows, C., Holly, J. M. P., Laurence, N. J., Vernon, E. G., Carter, J. V., Clark, M. A., McIntosh, J., McCaig, C., Winters, Z. E., Perks, C. M. (2006). Insulin-Like Growth Factor Binding Protein 3 Has Opposing Actions on Malignant and Nonmalignant Breast Epithelial Cells that Are Each Reversible and Dependent upon Cholesterol-Stabilized Integrin Receptor Complexes. Endocrinology 147: 3484-3500 [Abstract] [Full Text]  
• Izumi, K., Kurosaka, D., Iwata, T., Oguchi, Y., Tanaka, Y., Mashima, Y., Tsubota, K. (2006). Involvement of Insulin-like Growth Factor-I and Insulin-like Growth Factor Binding Protein-3 in Corneal Fibroblasts during Corneal Wound Healing. IOVS 47: 591-598 [Abstract] [Full Text]  
• Takaoka, M., Smith, C. E., Mashiba, M. K., Okawa, T., Andl, C. D., El-Deiry, W. S., Nakagawa, H. (2006). EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I. Am. J. Physiol. Gastrointest. Liver Physiol. 290: G404-G416 [Abstract] [Full Text]  
• Oh, S.-H., Kim, W.-Y., Kim, J.-H., Younes, M. N., El-Naggar, A. K., Myers, J. N., Kies, M., Cohen, P., Khuri, F., Hong, W. K., Lee, H.-Y. (2006). Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res. 12: 653-661 [Abstract] [Full Text]  
• Diorio, C., Berube, S., Byrne, C., Masse, B., Hebert-Croteau, N., Yaffe, M., Cote, G., Pollak, M., Brisson, J. (2006). Influence of Insulin-like Growth Factors on the Strength of the Relation of Vitamin D and Calcium Intakes to Mammographic Breast Density. Cancer Res. 66: 588-597 [Abstract] [Full Text]  
• Jenkins, P J, Khalaf, S, Ogunkolade, W, McCarthy, K, David, T, Hands, R E, Davies, D, Bustin, S A (2005). Differential expression of IGF-binding protein-3 in normal and malignant colon and its influence on apoptosis. Endocr Relat Cancer 12: 891-901 [Abstract] [Full Text]  
• Keku, T. O., Lund, P. K., Galanko, J., Simmons, J. G., Woosley, J. T., Sandler, R. S. (2005). Insulin Resistance, Apoptosis, and Colorectal Adenoma Risk. Cancer Epidemiol. Biomarkers Prev. 14: 2076-2081 [Abstract] [Full Text]  
• Diorio, C., Pollak, M., Byrne, C., Masse, B., Hebert-Croteau, N., Yaffe, M., Cote, G., Berube, S., Morin, C., Brisson, J. (2005). Insulin-Like Growth Factor-I, IGF-Binding Protein-3, and Mammographic Breast Density. Cancer Epidemiol. Biomarkers Prev. 14: 1065-1073 [Abstract] [Full Text]  
• Masaki, M., Kurisaki, T., Shirakawa, K., Sehara-Fujisawa, A. (2005). Role of Meltrin {alpha} (ADAM12) in Obesity Induced by High- Fat Diet. Endocrinology 146: 1752-1763 [Abstract] [Full Text]  
• Silha, J. V., Gui, Y., Mishra, S., Leckstrom, A., Cohen, P., Murphy, L. J. (2005). Overexpression of Gly56/Gly80/Gly81-Mutant Insulin-Like Growth Factor-Binding Protein-3 in Transgenic Mice. Endocrinology 146: 1523-1531 [Abstract] [Full Text]  
• Wilczak, N, Ramsaransing, G S., Mostert, J, Chesik, D, De Keyser, J (2005). Serum levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in relapsing and primary progressive multiple sclerosis. Mult Scler 11: 13-15 [Abstract]  
• Takaoka, M., Harada, H., Andl, C. D., Oyama, K., Naomoto, Y., Dempsey, K. L., Klein-Szanto, A. J., El-Deiry, W. S., Grimberg, A., Nakagawa, H. (2004). Epidermal Growth Factor Receptor Regulates Aberrant Expression of Insulin-Like Growth Factor-Binding Protein 3. Cancer Res. 64: 7711-7723 [Abstract] [Full Text]  
• Lee, H.-Y., Moon, H., Chun, K.-H., Chang, Y.-S., Hassan, K., Ji, L., Lotan, R., Khuri, F. R., Hong, W. K. (2004). Effects of Insulin-like Growth Factor Binding Protein-3 and Farnesyltransferase Inhibitor SCH66336 on Akt Expression and Apoptosis in Non-Small-Cell Lung Cancer Cells. JNCI J Natl Cancer Inst 96: 1536-1548 [Abstract] [Full Text]  
• Kuemmerle, J. F., Murthy, K. S., Bowers, J. G. (2004). IGFBP-3 activates TGF-{beta} receptors and directly inhibits growth in human intestinal smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 287: G795-G802 [Abstract] [Full Text]  
• Pold, M., Krysan, K., Pold, A., Dohadwala, M., Heuze-Vourc'h, N., Mao, J. T., Riedl, K. L., Sharma, S., Dubinett, S. M. (2004). Cyclooxygenase-2 Modulates the Insulin-Like Growth Factor Axis in Non-Small-Cell Lung Cancer. Cancer Res. 64: 6549-6555 [Abstract] [Full Text]  
• Fraga, M. F., Herranz, M., Espada, J., Ballestar, E., Paz, M. F., Ropero, S., Erkek, E., Bozdogan, O., Peinado, H., Niveleau, A., Mao, J.-H., Balmain, A., Cano, A., Esteller, M. (2004). A Mouse Skin Multistage Carcinogenesis Model Reflects the Aberrant DNA Methylation Patterns of Human Tumors. Cancer Res. 64: 5527-5534 [Abstract] [Full Text]  
• Baege, A. C., Disbrow, G. L., Schlegel, R. (2004). IGFBP-3, a Marker of Cellular Senescence, Is Overexpressed in Human Papillomavirus-Immortalized Cervical Cells and Enhances IGF-1-Induced Mitogenesis. J. Virol. 78: 5720-5727 [Abstract] [Full Text]  
• Hathaway, M. R., Dayton, W. R., White, M. E., Pampusch, M. S. (2003). Effects of antimicrobials and weaning on porcine serum insulin-like growth factor binding protein levels. J ANIM SCI 81: 1456-1463 [Abstract] [Full Text]  
• Smid-Koopman, E., Blok, L. J., Kuhne,, L. C. M., Burger, C. W., Helmerhorst, T. J. M., Brinkman, A. O., Huikeshoven, F. J. (2003). Distinct Functional Differences of Human Progesterone Receptors A and B on Gene Expression and Growth Regulation in Two Endometrial Carcinoma Cell Lines. Reproductive Sciences 10: 49-57 [Abstract]  
• Chang, Y. S., Wang, L., Liu, D., Mao, L., Hong, W. K., Khuri, F. R., Lee, H.-Y. (2002). Correlation between Insulin-like Growth Factor-binding Protein-3 Promoter Methylation and Prognosis of Patients with Stage I Non-Small Cell Lung Cancer. Clin. Cancer Res. 8: 3669-3675 [Abstract] [Full Text]  
• Tanno, B., Negroni, A., Vitali, R., Pirozzoli, M. C., Cesi, V., Mancini, C., Calabretta, B., Raschella, G. (2002). Expression of Insulin-like Growth Factor-binding Protein 5 in Neuroblastoma Cells Is Regulated at the Transcriptional Level by c-Myb and B-Myb via Direct and Indirect Mechanisms. J. Biol. Chem. 277: 23172-23180 [Abstract] [Full Text]  
• Tsubaki, J., Hwa, V., Twigg, S. M., Rosenfeld, R. G. (2002). Differential Activation of the IGF Binding Protein-3 Promoter by Butyrate in Prostate Cancer Cells. Endocrinology 143: 1778-1788 [Abstract] [Full Text]