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IGFBP-3 and apoptosis—a licence to kill?

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Abstract

Insulin-like growth factor binding protein (IGFBP)-3, the major carrier of insulin-like growth factors (IGFs) in the circulation, was first isolated and characterised over a decade ago. More recently, IGFBP-3 has been assigned a role as a putative death-promoting factor, a function that appears, under certain circumstances, to be independent of its IGF-binding ability. This review examines the current evidence for a pro-apoptotic function for IGFBP-3 and speculates on its physiological significance.

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References

  1. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: Biological actions. Endocrine Rev 1995; 16: 3-34.

    Google Scholar 

  2. Nissley P, Lopaczynski W. Insulin-like growth factor receptors. Growth Factors 1991; 5: 29-43.

    Google Scholar 

  3. Kulik G, Klippel A, Weber MJ. Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol 1997; 17: 1595-1606.

    Google Scholar 

  4. Parrizas M, Saltiel AR, LeRoith D. Insulin-like growth factor I inhibits apoptosis using the phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. J Biol Chem 1997; 272: 154-161.

    Google Scholar 

  5. Butt AJ, Firth SM, Baxter RC. The IGF axis and programmed cell death. Immunol Cell Biol 1999; 77: 256-262.

    Google Scholar 

  6. Parrizas M, LeRoith D. Insulin-like growth factor-1 inhibition of apoptosis is associated with increased expression of the bcl-xL gene product. Endocrinology 1997; 138: 1355-1358.

    Google Scholar 

  7. Singleton JR, Dixit VM, Feldman EL. Type I insulin-like growth factor receptor activation regulates apoptotic proteins. J Biol Chem 1996; 271: 31791-31794.

    Google Scholar 

  8. Wang L, Ma W, Markovich R, Lee W-L, Wang PH. Insulin-like growth factor I modulates induction of apoptotic signalling in H9C2 cardiac muscle cells. Endocrinology 1998; 139: 1354-1360.

    Google Scholar 

  9. Shimasaki S, Ling N. Identification and molecular characterisation of insulin-like growth factor binding proteins (IGFBP-1,-2,-3,-4,-5, and-6). Prog Growth Factor Res 1991; 3: 243-266.

    Google Scholar 

  10. Baxter RC. Insulin-like growth factor binding proteins in the human circulation: A review. Horm Res 1994; 42: 140-144.

    Google Scholar 

  11. De Mellow JS, Baxter RC. Growth hormone-dependent insulin-like growth factor (IGF) binding protein both inhibits and potentiates IGF-I-stimulated DNA synthesis in human skin fibroblasts. Biochem Biophys Res Comm 1988; 156: 199-204.

    Google Scholar 

  12. Conover CA. Potentiation of insulin-like growth factor (IGF) action by IGF-binding protein-3: Studies of underlying mechanism. Endocrinology 1992; 130: 3191-3199.

    Google Scholar 

  13. Chen J-C, Shao Z-M, Sheikh MS, et al. Insulin-like growth factor-binding protein enhancement of insulin-like growth factor-1 (IGF-1)-mediated DNA synthesis and IGF-1 binding in a human breast carcinoma cell line. J Cell Physiol 1998; 158: 69-78.

    Google Scholar 

  14. Baxter RC. Molecular aspects of insulin-like growth factor binding proteins. In: LeRoith D, ed. Advances in Molecular and Cellular Endocrinology. Greenwich: JAI Press 1997: 123-159.

    Google Scholar 

  15. Firth SM, Fanayan S, Benn D, Baxter RC. Development of resistance to insulin-like growth factor binding protein-3 in transfected T47D breast cancer cells. Biochem Biophys Res Commun 1998; 246: 325-329.

    Google Scholar 

  16. MacDonald RG, Schaffer BS, Kang IJ, Hong SM, Kim EJ, Park JH. Growth inhibition and differentiation of the human colon carcinoma cell line, Caco-2, by constitutive expression of insulin-like growth factor binding protein-3. J Gastroenterol Hepatol 1999; 14: 72-78.

    Google Scholar 

  17. Cohen P, Lamson G, Okajima T, Rosenfeld RG. Transfection of the human IGFBP-3 gene into BALB/c fibroblasts-a model for the cellular functions of IGFBPs. Growth Reg 1993; 3: 23-26.

    Google Scholar 

  18. Oh Y, Muller HL, Lamson G, Rosenfeld RG. Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells. J Biol Chem 1993; 268: 14964-14971.

    Google Scholar 

  19. Valentinis B, Bhala A, DeAngelis T, Baserga R, Cohen P. The human insulin-like growth factor (IGF) binding protein-3 inhibits the growth of fibroblasts with a targeted disruption of the IGF-I receptor gene. Mol Endocrinol 1995; 9: 361-367.

    Google Scholar 

  20. Lalou C, Lassarre C, Binoux M. A proteolytic fragment of insulin-like growth factor (IGF) binding protein-3 that fails to bind to IGFs inhibits the mitogenic effects of IGF-I and insulin. Endocrinology 1996; 137: 3206-3212.

    Google Scholar 

  21. Zadeh SM, Binoux M. The 16-kDa proteolytic fragment of insulin-like growth factor (IGF) binding protein-3 inhibits the mitogenic action of fibroblast growth factor on mouse fibroblasts with a targeted disruption of the type 1 IGF receptor gene. Endocrinology 1997; 138: 3069-3072.

    Google Scholar 

  22. Murphy LJ, Molnar P, Lu X, Huang H. Expression of human insulin-like growth factor-binding protein-3 in transgenic mice. J Mol Endo 1995; 15: 293-303.

    Google Scholar 

  23. Gucev ZS, Oh Y, Kelley KM, Rosenfeld RG. Insulin-like growth factor binding protein 3 mediates retinoic acid-and transforming growth factor ? 2-induced growth inhibition in human breast cancer cells. Cancer Res 1996; 56: 1545-1550.

    Google Scholar 

  24. Hembree JR, Agarwal C, Beard RL, Chandraratna RA, Eckert R. Retinoid X receptor-specific retinoids inhibit the ability of retinoic acid receptor-specific retinoids to increase the level of insulin-like growth factor binding protein-3 in human ectocervical epithelial cells. Cancer Res 1996; 56: 1794-1799.

    Google Scholar 

  25. Yateman ME, Claffey DC, Cwyfan Hughes SC, Frost VJ, Wass JA, Holly JM. Cytokines modulate the sensitivity of human fibroblasts to stimulation with insulin-like growth factor-I (IGF-I) by altering endogenous IGF-binding protein production. J Endocrinol 1993; 137: 151-159.

    Google Scholar 

  26. Rozen F, Zhang J, Pollak M. Antiproliferative action of tumor necrosis factor-? on MCF-7 breast cancer cells is associated with increased insulin-like growth factor binding protein-3 accumulation. Int J Oncol 1998; 13: 865-869.

    Google Scholar 

  27. Huynh H, Yang X, Pollak M. Estradiol and antiestrogens regulate a growth inhibitory insulin-like growth factor binding protein 3 autocrine loop in human breast cancer cells. J Biol Chem 1996; 271: 1016-1021.

    Google Scholar 

  28. Buckbinder L, Talbott R, Velasco-Miguel S, et al. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 1995; 377: 646-649.

    Google Scholar 

  29. Oh Y, Gucev Z, Ng L, Muller HL, Rosenfeld RG. Antiproliferative actions of insulin-like growth factor binding protein (IGFBP)-3 in human breast cancer cells. Prog Growth Factor Res 1998; 6: 503-512.

    Google Scholar 

  30. Huynh H, Pollak M, Zhang JC. Regulation of insulin-like growth factor (IGF) II and IGF binding protein 3 autocrine loop in human PC-3 prostate cancer cells by vitamin D metabolite 1,25(OH)2D3 and its analog EB1089. Int J Oncol 1998; 13: 137-143.

    Google Scholar 

  31. Colston KW, Perks CM, Xie SP, Holly JMP. Growth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3. J Mol Endo 1998; 20: 157-162.

    Google Scholar 

  32. Agarwal C, Lambert A, Chandraratna RAS, Rorke EA, Eckert RL. Vitamin D regulates human ectocervical epithelial cell proliferation and insulin-like growth factor-binding protein-3 level. Biol Reprod 1999; 60: 567-572.

    Google Scholar 

  33. Martin JL, Ballesteros M, Baxter RC. Insulin-like growth factor-I (IGF-I) and transforming growth factor-beta 1 release IGF-binding protein-3 from human fibroblasts by different mechanisms. Endocrinology 1992; 131: 1703-1710.

    Google Scholar 

  34. Oh Y, Muller HL, Ng L, Rosenfeld RG. Transforming growth factor-beta-induced cell growth inhibition in human breast cancer cells is mediated through insulin-like growth factor-binding protein-3 action. J Biol Chem 1995; 270: 13589-13592.

    Google Scholar 

  35. Cohen P, Rajah R, Rosenbloom J, Herrick DJ. IGFBP-3 mediates TGF-? 1-induced cell growth in human airway smooth muscle cells. Am J Physiol 2000; 278: L545-L551.

    Google Scholar 

  36. Hembree JR, Agarwal C, Eckert RL. Epidermal growth factor suppresses insulin-like growth factor binding protein 3 levels in human papillomavirus type 16-immortalized cervical epithelial cells and thereby potentiates the effects of insulin-like growth factor 1. Cancer Res 1994; 54: 3160-3166.

    Google Scholar 

  37. Edmondson SR, Murashita MM, Russo VC, Wraight CJ, Werther GA. Expression of insulin-like growth factor binding protein-3 (IGFBP-3) in human keratinocytes is regulated by EGF and TGF?1. J Cell Physiol 1999; 179: 201-207.

    Google Scholar 

  38. Nishimura A, Fujimoto M, Oguchi S, Fusunyan RD, MacDermott RP, Sanderson IR. Short-chain fatty acids regulate IGF-binding protein secretion by intestinal epithelial cells. Am J Physiol 1998; 275: E55-63.

    Google Scholar 

  39. Oh Y, Muller HL, Pham H, Rosenfeld RG. Demonstration of receptors for insulin-like growth factor binding protein-3 on Hs578T human breast cancer cells. J Biol Chem 1993; 268: 26045-26048.

    Google Scholar 

  40. Yamanaka Y, Fowles JL, Wilson EM, Rosenfeld RG, Oh Y. Characterisation of insulin-like growth factor binding protein-3 (IGFBP-3) binding to human breast cancer cells: Kinetics of IGFBP-3 binding and identification of receptor binding domain on the IGFBP-3 molecule. Endocrinology 1999; 140: 1319-1328.

    Google Scholar 

  41. Firth SM, Ganeshprasad U, Baxter RC. Structural determinants of ligand and cell surface binding of insulin-like growth factorbinding protein-3. J Biol Chem 1998; 273: 2631-2638.

    Google Scholar 

  42. Leal SM, Liu Q, Huang SS, Huang JS. The type V transforming growth factor ? receptor is the putative insulin-like growth factor-binding protein 3 receptor. J Biol Chem 1998; 272: 20572-20576.

    Google Scholar 

  43. Leal SM, Huang SS, Huang JS. Interactions of high affinity insulin-like growth factor-binding proteins with the type V transforming growth factor-? receptor in mink lung epithelial cells. J Biol Chem 1999; 274: 6711-6717.

    Google Scholar 

  44. Fanayan S, Firth SM, Butt AJ, Baxter RC. Growth inhibition by insulin-like growth factor binding protein-3 in T47D breast cancer cells requires transforming growth factor-? (TGF-?) and the type II TGF-? receptor. J Biol Chem 2000; 275: 39146-39151.

    Google Scholar 

  45. Martin JL, Baxter RC. Oncogenic ras causes resistance to the growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3) in breast cancer cells. J Biol Chem 1999; 274: 16407-16411.

    Google Scholar 

  46. Radulescu RT. Nuclear localisation signal in insulin-like growth factor-binding protein 3. TIBS 1994; 19: 278.

    Google Scholar 

  47. LiW, Fawcett J, Widmer HR, Fielder PJ, Rabkin R, Keller GA. Nuclear transport of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in opossum kidney cells. Endocrinology 1997; 138: 1763-1766.

    Google Scholar 

  48. Jacques G, Noll K, Wegmann B, et al. Nuclear localisation of insulin-like growth factor binding protein 3 in a lung cancer cell line. Endocrinology 1997; 138: 1767-1770.

    Google Scholar 

  49. Wraight CJ, Liepe IJ, White PJ, Hibbs AR, Werther GA. Intranuclear localization of insulin-like growth factor binding protein-3 (IGFBP-3) during cell division in human keratinocytes. J Invest Dermatol 1998; 111: 239-242.

    Google Scholar 

  50. Schedlich LJ, Young TY, Firth SM, Baxter RC. Insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 share a common nuclear transport pathway in T47D human breast carcinoma cells. J Biol Chem 1998; 273: 18347-18352.

    Google Scholar 

  51. Schedlich LJ, Le Page S, Firth SM, Briggs LJ, Jans DA, Baxter RC. Nuclear import of insulin-like growth factor binding protein-3 (IGFBP-3) and IGFBP-5 is mediated by the importin ? subunit. J Biol Chem 2000; 275: 23462-23470.

    Google Scholar 

  52. Liu B, Lee HY, Weinzimer SA, et al. Direct functional interactions between IGFBP-3 and RXR-? regulate transcriptional signalling and apoptosis. J Biol Chem 2000; 275: 33607-33613.

    Google Scholar 

  53. Resnicoff M, Abraham D, Yutanawiboonchai W, et al. The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. Cancer Res 1995; 55: 2463-2469.

    Google Scholar 

  54. Shen L, Glazer RI. Induction of apoptosis in glioblastoma cells by inhibition of protein kinase C and its association with the rapid accumulation of p53 and induction of the insulin-like growth factor-1 binding protein 3. Biochem Pharm 1998; 55: 1711-1719.

    Google Scholar 

  55. Shen L, Dean NM, Glazer RI. Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase C? antisense oligonucletide. Mol Pharm 1999; 55: 396-402.

    Google Scholar 

  56. Nickerson T, Huynh H. Vitamin D analogue EB1089-induced apoptosis prostate regression is associated with increased gene expression of insulin-like growth factor binding proteins.J Endocrinol 1999; 160: 223-229.

    Google Scholar 

  57. Rajah R, Valentinis B, Cohen P. Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-? 1 on programmed cell death through a p53-and IGF-independent mechanism. J Biol Chem 1997; 272: 12181-12188.

    Google Scholar 

  58. Rajah R, Khare A, Lee PDK, Cohen P. Insulin-like growth factor-binding protein-3 is partially responsible for highserum-induced apoptosis in PC-3 prostate cancer cells. J Endocrinol 1999; 163: 487-494.

    Google Scholar 

  59. Williams AC, Collard TJ, Perks CM, et al. Increased p53-dependent apoptosis by the insulin-like growth factor binding protein IGFBP-3 in human colonic adenoma derived cells. Cancer Res 2000; 60: 22-27.

    Google Scholar 

  60. Butt AJ, Firth S, King MA, Baxter RC. Insulin-like growth factor binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells. J Biol Chem 2000; 275: 39174-39181.

    Google Scholar 

  61. Gill ZP, Perks CM, Newcomb PV, Holly JMP. Insulin-like growth factor-binding protein (IGFBP)-3 predisposes breast cancer cells to programmed cell death in a non-IGF-dependent manner. J Biol Chem 1997; 272: 25602-25607.

    Google Scholar 

  62. Friedlander P, Haupt Y, Prives C, Oren M. A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis. Mol Cell Biol 1996; 16: 4961-4971.

    Google Scholar 

  63. Ludwig RL, Bates S, Vousden KH. Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol Cell Biol 1996; 16: 4952-4960.

    Google Scholar 

  64. Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol 1994; 124: 1-6.

    Google Scholar 

  65. Sedlak TW, Oltvai ZN, Yang E, et al. Multiple Bcl-2 family members demonstrate selective dimerisations with Bax. Proc Natl Acad Sci USA 1995; 92: 7834-7838.

    Google Scholar 

  66. Toms SA, Hercbergs A, Liu J, et al. Antagonist effect of insulin-like growth factor I on protein kinase-mediated apoptosis in human glioblastoma cells in association with bcl-2 and bcl-xL. J Neurosurg 1998; 88: 884-889.

    Google Scholar 

  67. Suzuki J, Kaziro Y, Koide H. Synergistic action of R-Ras and IGF-I on Bcl-xL expression and caspase-3 inhibition in BaF3 cells: R-Ras and IGF-I control distinct anti-apoptotic kinase pathways. FEBS Lett 1998; 437: 112-116.

    Google Scholar 

  68. Navarro P, Valverde AM, Benito M, Lorenzo M. Insulin/IGF-I rescues immortalized brown adipocytes from apoptosis downregulating Bcl-xS expression, in a PI 3-kinase-and MAP kinase-dependent manner. Exp Cell Res 1998; 243: 213-221.

    Google Scholar 

  69. MiyashitaT, Krajewski S, Krajewska M, et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 1994; 9: 1799-1805.

    Google Scholar 

  70. Butt AJ, Kumar S. Caspases: The molecular effectors of apoptosis. In: Lavin M, Watters D, eds. Signalling pathways in apoptosis. UK: Harwood Academic Publishers, 1999: 247-262.

    Google Scholar 

  71. Jung Y-K, Miura M, Yuan J. Suppression of Interleukin-1 ?-converting enzyme-mediated cell death by insulin-like growth factor. J Biol Chem 1996; 271: 5112-5117.

    Google Scholar 

  72. Mannhardt B, Weinzimer SA, Wagner M, et al. Human papillomavirus type 16 E7 oncoprotein binds and inactivates growthinhibitory insulin-like growth factor binding protein 3. Mol Cell Biol 2000; 20: 6483-6495.

    Google Scholar 

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Authors and Affiliations

  1. Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia

    A. J. Butt

  2. Cancer Research Campaign Colorectal Tumour Biology Research Group, Department of Pathology and Microbiology, University of Bristol, Bristol, United Kingdom

    A. C. Williams

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Butt, A.J., Williams, A.C. IGFBP-3 and apoptosis—a licence to kill?. Apoptosis 6, 199–205 (2001). https://doi.org/10.1023/A:1011388710719

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