Horm Metab Res 2003; 35(11/12): 726-733
DOI: 10.1055/s-2004-814146
Review
© Georg Thieme Verlag Stuttgart · New York

Epidemiology and Biology of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) as an Anti-cancer Molecule

O.  Ali1 , P.  Cohen1 , K.-W.  Lee1
  • 1Mattel Children’s Hospital at UCLA
Further Information

Publication History

Received 6 September 2003

Accepted after Revision 23 October 2003

Publication Date:
07 January 2004 (online)

Abstract

The Insulin-like Growth Factor (IGF) signaling system plays a central role in cellular growth, differentiation and proliferation. IGFBP-3 is the most abundant IGF binding protein in human serum and has been shown to be a growth inhibitory, apoptosis-inducing molecule, capable of acting via IGF-dependent and IGF-independent mechanisms. Over the last decade, several clinical studies have proposed that individuals with IGFBP-3 levels in the upper range of normal may have a decreased risk for certain common cancers. This includes evidence of a protective effect against breast cancer, prostate cancer, colorectal cancer, and lung cancer. In addition, a series of in vitro studies and animal experiments point towards an important role for IGFBP-3 in the regulation of cell growth and apoptosis. In this brief review, we discuss the biological role of IGFBP-3 and summarize the epidemiological and experimental evidence suggesting a role for IGFBP-3 as an anti-cancer molecule.

References

  • 1 Cohen P, Rosenfeld R G. Physiologic and clinical relevance of the insulin-like growth factor binding proteins.  Curr Opin Pediatr. 1994;  6 462-467
  • 2 Hasegawa T, Cohen P, Rosenfeld R G. Characterization of the insulin-like growth factor axis in TM 3 Leydig cells.  Growth Reg. 1995;  5 151-159
  • 3 Katz L EL, Rosenfeld R G, Cohen P. Clinical significance of insulin-like growth factor binding proteins (IGFBPs).  Endocrinologist. 1995;  5 36-43
  • 4 Firth S M, Baxter R C. Cellular actions of the insulin-like growth factor binding proteins.  Endocr Rev. 2002;  23 824-854 [Review]
  • 5 Weinzimer S A, Cohen P. Biological significance of insulin-like growth factor binding proteins. In: Matera L, Rapaport R (eds) Growth and Lactogenic Hormones. Amsterdam; Elsevier Science B.V 2002: 37-52;
  • 6 Collett-Solberg P F, Cohen P. Genetics, chemistry, and function of the IGF/IGFBP system.  Endocrine. 2000;  12 121-136 [Review]
  • 7 Schmid C, Ghirlanda-Keller C, Zapf J. Effects of IGF-1 and -II, IGF binding protein-3 (IGFBP-3), and transforming growth factor-beta (TGF-beta) on growth and apoptosis of human osteosarcoma Saos-2/B-10 cells: lack of IGF-independent IGFBP-3 effects.  Eur J Endocrinol. 2001;  145 213-221
  • 8 De Mellow J SM, Baxter R C. Growth hormone-dependent insulin-like growth factor (IGF) binding protein both inhibits and potentiates IGF-1-stimulated DNA synthesis in human skin fibroblasts.  Biochem Biophys Res Commun. 1988;  156 199-204
  • 9 Moerman E J, Thweatt R, Moerman A M, Jones R A, Goldstein S. Insulin-like growth factor binding protein-3 is overexpressed in senescent and quiescent human fibroblasts.  Exp Gerontol. 1993;  28 361-370
  • 10 Li Y M, Schacher D H, Liu Q. et al . Regulation of myeloid growth and differentiation by the insulin-like growth factor I receptor.  Endocrinol. 1997;  138 362-368
  • 11 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-1 receptor gene.  Mol Endocrinol. 1995;  9 361-367
  • 12 Buckway C K, Wilson E M, Ahlsen M, Bang P, Oh Y, Rosenfeld R G. Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding.  J Clin Endocrinol Metab. 2001;  86 4943-4950
  • 13 Rajah R, Valentis B, Cohen P. Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-β1 on programmed cell death via a p53- and IGF-independent mechanism.  J Biol Chem. 1997;  272 12 181-12 188
  • 14 Giuliano M, Lauricella M, Vassallo E, Carabillo M, Vento R, Tesoriere G. Induction of apoptosis in retinoblastoma cells by topoisomerase inhibitors.  Invest Ophthalmol Vis Sci. 1998;  39 1300-1311
  • 15 Shen L, Dean N, Glazer R. Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase C-alpha antisense oligonucleotide.  Mol Pharmacol. 1999;  55 396-402
  • 16 Han G R, Dohi D F, Lee H Y. et al . All-trans-retinoic acid increases transforming growth factor-beta2 and insulin-like growth factor binding protein-3 expression through a retinoicacid receptor-alpha-dependent signaling pathway.  J Biol Chem. 1997;  272 13 711-13 716
  • 17 Huynh H, Yang Y F, 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
  • 18 Gucev Z S, Oh Y, Kelley K M, Rosenfeld R G. Insulin-like growth factor binding protein 3 mediaties retinoic acid- and transforming growth factor β2-induced growth inhibition in human breast cancer cells.  Cancer Res. 1996;  56 1545-1550
  • 19 Erondu N E, Dake B L, Moser D R, Lin M, Boes M, Bar R S. Regulation of endothelial IGFBP-3 synthesis and secretion by IGF-1 and TGF-beta.  Growth Reg. 1996;  6 1-9
  • 20 Rajah R, Lee K W, Cohen P. Insulin-like growth factor binding protein-3 mediates tumor necrosis factor-alpha-induced apoptosis: role of Bcl-2 phosphorylation.  Cell Growth Differ. 2002;  13 163-171
  • 21 Boyle B J, Zhao X Y, Cohen P, Feldman D. Insulin-like growth factor binding protein-3 mediates 1 alpha,25-dihydroxyvitamin d(3) growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1.  J Urol. 2001;  165 1319-1324
  • 22 Katayama M L, Pasini F S, Folgueira M A, Snitcovsky I M, Brentani M M. Molecular targets of 1,25(OH)2D3 in HC11 normal mouse mammary cell line.  J Steroid Biochem Mol Biol. 2003;  84 57-69
  • 23 Spoerri P E, Caballero S, Wilson S H, Shaw L C, Grant M B. Expression of IGFBP-3 by human retinal endothelial cell cultures: IGFBP-3 involvement in growth inhibition and apoptosis.  Invest Ophthalmol Vis Sci. 2003;  44 365-369
  • 24 Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger B R, Kley N. Induction of the growth inhibitor IGF-binding protein 3 by p53.  Nature. 1995;  377 646-649
  • 25 Butt A J, Firth S M, King M A, Baxter R C. 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 39 174-39 181
  • 26 Oh Y, Müller H L, Lamson G, Rosenfeld R G. Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells. Cell surface binding and growth inhibition.  J Biol Chem. 1993;  268 14 964-14 971
  • 27 Oh Y, Müller H L, Pham H, Rosenfeld R G. Demonstration of receptors for insulin-like growth factor binding protein-3 on Hs578T human breast cancer cells.  J Biol Chem. 1993;  268 26 045-26 048
  • 28 Ingermann A R, Kim H S, Oh Y. Characterization of a functional receptor for insulin-like growth factor binding protein 3.  Growth Horm IGF Res. 2000;  10 A27
  • 29 Liu B, Lee H Y, Weinzimer S A. et al . Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-alpha regulate transcriptional signaling and apoptosis.  J Biol Chem. 2000;  275 33 607-33 613
  • 30 Rajah R, Katz L, Nunn S, Solberg P, Beers T, Cohen P. Insulin-like growth factor binding protein proteases: functional regulators of cell growth.  Prog Growth Factor Res. 1996;  6 273-284
  • 31 Cohen P, Peehl D M, Graves H C, Rosenfeld R G. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease.  J Endocrinol. 1994;  142 407-415
  • 32 Manes S, Llorente M, Lacalle R, Gomez-Mouton C, Kremer L, Mira E, Martinez-A C. The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells.  J Biol Chem. 1999;  274 6935-6945
  • 33 Nunn S, Beers Gibson T, Rajah R, Cohen P. Regulation of prostate cell growth by the insulin-like growth factor binding proteins and their proteases.  Endocrine. 1997;  7 115-118
  • 34 Modric T, Silha J V, Shi Z, Gui Y, Suwanichkul A, Durham S K, Powell D R, Murphy L J. Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice.  Endocrinology. 2001;  142 1958-1967
  • 35 Silha J V, Murphy L J. Minireview: Insights from insulin-like growth factor binding protein transgenic mice.  Endocrinology. 2002;  143 3711-3714
  • 36 Pintar J E. Single and multiple knockouts of the IGFBPs. Program of the 83rd Annual Meeting of The Endocrine Society. Denver; CO 2001: 44
  • 37 Hochscheid R, Jaques G, Wegmann B. Transfection of human insulin-like growth factor-binding protein 3 gene inhibits cell growth and tumorigenicity: a cell culture model for lung cancer.  J Endocrinol. 2000;  166 553-563
  • 38 Lee H Y, Chun K H, Liu B, Wiehle S A, Cristiano R J, Hong W K, Cohen P, Kurie J M. Insulin-like growth factor binding protein-3 inhibits the growth of non-small cell lung cancer.  Cancer Res. 2002;  62 3530-3537
  • 39 Devi G R, Sprenger C C, Plymate S R, Rosenfeld R G. Insulin-like growth factor binding protein-3 induces early apoptosis in malignant prostate cancer cells and inhibits tumor formation in vivo.  Prostate. 2002;  51 141-52
  • 40 Liu B, Li H, Ma L, Mascarenhas D, Chandraratna R, Cohen P. RXR-specific ligands potentiate IGFBP-3 actions on tumor apoptosis in vitro and in vivo by stabilizing nuclear IGFBP-3. Abstract. Philadelphia; Endocrine Society Meetings 2003
  • 41 Portera C A Jr, Shinohara H, Mima T, Miller A, Tsan R, Mascarenhas D, Radinsky R. Targeting the insulin-like growth factor axis in the therapy of colorectal carcinoma liver metastasis.  Growth Horm IGF Res. 2000;  10 Suppl A S47-48
  • 42 Singh R P, Dhanalakshmi S, Tyagi A K, Chan D C, Agarwal C, Agarwal R. Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels.  Cancer Res. 2002;  62 3063-3069
  • 43 Liu C, Lian F, Smith D E, Russell R M, Wang X D. Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in cigarette smoke-exposed ferrets.  Cancer Res. 2003;  63 3138-3144
  • 44 Gupta S, Hastak K, Ahmad N, Lewin J S, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols.  Proc Natl Acad Sci USA. 2001;  98 10 350-10 355
  • 45 Chan J M, Stampfer M J, Giovanucci E. et al . Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study.  Science. 1998;  279 563-566
  • 46 Chan J M, Stampfer M J, Ma J. et al . Insulin-like growth factor-I (IGF-1) and IGF binding protein-3 as predictors of advanced-stage prostate cancer.  J Natl Cancer Inst. 2002;  94 1099-1106
  • 47 Chokkalingam A P, Pollak M, Fillmore C M. et al . Insulin-like growth factors and prostate cancer: a population-based case-control study in China.  Cancer Epidemiol Biomarkers Prev. 2001;  10 421-427
  • 48 Palmqvist R, Hallmans G, Rinaldi S. et al . Plasma insulin-like growth factor I, insulin-like growth factor binding protein-3, and risk of colorectal cancer: a prospective study in Northern Sweden.  Gut. 2002;  50 642-646
  • 49 Ma J, Polak M N, Giovanucci E. et al . Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3.  J Natl Cancer Inst. 1999;  91 620-625
  • 50 Giovanucci E, Pollak M N, Platz E A. et al . A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women.  Cancer Epidemiol Biomarkers Prev. 2000;  9 345-349
  • 51 Wakai K, Ito Y, Suzuki K. et al . Serum insulin-like growth factors, insulin-like growth factor-binding protein-3, and risk of lung cancer death: a case-control study nested in the Japan Collaborative Cohort (JACC) study.  Jpn J Cancer Res. 2002;  93 1279-1286
  • 52 Zhao H, Grossman H B, Spitz M R. et al . Plasma levels of insulin-like growth factor-1 and binding protein-3, and their association with bladder cancer risk.  J Urol. 2003;  169 714-717
  • 53 Petridou E, Skalkidou A, Dessypris N, Moustaki M, Mantzoros C, Spanos E, Trichopoulos D. Insulin-like growth factor binding protein-3 predicts survival from acute childhood leukemia.  Oncology. 2001;  60 252-257
  • 54 Toniolo P, Bruning P F, Akhmedekhanov A. et al . Serum insulin-like growth factor-I and breast cancer.  Int J Cancer. 2000;  88 828-832
  • 55 Hankinson S E, Willett W C, Colditz G A. et al . Circulating concentrations of insulin-like growth factor-I and risk of breast cancer.  Lancet. 1998;  351 1393-1396
  • 56 Kaaks R, Lundin E, Rinaldi S. et al . Prospective study of IGF-1, IGF-binding proteins, and breast cancer risk, in northern and southern Sweden.  Cancer Causes Control. 2002;  13 307-316
  • 57 Krajcik R A, Borofsky N D, Massardo S, Orenteich N. Insulin-like growth factor I (IGF-1), IGF-binding proteins, and breast cancer.  Cancer Epidemiol Biomarkers Prev. 2002;  11 1566-1573
  • 58 Del Giudice M E, Fantus I G, Ezzat S. et al . Insulin and related factors in premenopausal breast cancer risk.  Breast Cancer Res Treat. 1998;  47 111-120
  • 59 Yu H, Jin F, Shu X O. et al . Insulin-like growth factors and breast cancer risk in Chinese women.  Cancer Epidemiol Biomarkers Prev. 2002;  11 705-712
  • 60 Byrne C, Colditz G A, Willett W C, Speizer F E, Pollak M, Hankinson S E. Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density.  Cancer Res. 2000;  60 3744-3748
  • 61 Firth S M, Fanayan S, Benn D, Baxter R C. 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
  • 62 Spitz M R, Barnett M J, Goodman G E. et al . Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the Beta-Carotene and Retinol Efficacy Trial Cohort.  Cancer Epidemiol Biomarkers Prev. 2002;  11 1413-1418
  • 63 Kaaks R, Toniolo P, Akhmedkhanov A. et al . Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women.  J Natl Cancer Inst. 2000;  92 1592-1600
  • 64 Probst-Hensch N M, Yuan J M, Stanczyk F Z. et al . IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort of Chinese men in Shanghai.  Br J Cancer. 2001;  85 1695-1699
  • 65 Shim M, Cohen P. IGFs and human cancer: implications regarding the risk of growth hormone therapy.  Horm Res. 1999;  51 Suppl 3 42-51
  • 66 LeRoith D, Roberts C T. The insulin-like growth factor system and cancer.  Cancer Letters. 2003;  195 127-137
  • 67 Peters G, Gongoll S, Langner C, Mengel M, Piso P, Klempnauer J, Ruschoff J, Kreipe H, von Wasielewski R. IGF-1R, IGF-1 and IGF-2 expression as potential prognostic and predictive markers in colorectal-cancer.  Virchows Arch. 2003;  443 139-145 [Epub 2003 Jul 05]
  • 68 Renehan A G, Painter J E, O'Halloran D, Atkin W S, Potten C S, O'Dwyer S T, Shalet S M. Circulating insulin-like growth factor II and colorectal adenomas.  J Clin Endocrinol Metab. 2000;  85 3402-3408
  • 69 Hunt K J, Toniolo P, Akhmedkhanov A, Lukanova A, Dechaud H, Rinaldi S, Zeleniuch-Jacquotte A, Shore R E, Riboli E, Kaaks R. Insulin-like growth factor II and colorectal cancer risk in women.  Cancer Epidemiol Biomarkers Prev. 2002;  11 901-905
  • 70 Wang L, Habuchi T, Tsuchiya N, Mitsumori K, Ohyama C, Sato K, Kinoshita H, Kamoto T, Nakamura A, Ogawa O, Kato T. Insulin-like growth factor-binding protein-3 gene -202 A/C polymorphism is correlated with advanced disease status in prostate cancer.  Cancer Res. 2003;  63 4407-4411
  • 71 Schernhammer E S, Hankinson S E, Hunter D J, Blouin M J, Pollak M N. Polymorphic variation at the -202 locus in IGFBP3: Influence on serum levels of insulin-like growth factors, interaction with plasma retinol and vitamin D and breast cancer risk.  Int J Cancer. 2003 Oct 20;  107 60-64

P. Cohen, M. D. 

UCLA Division of Endocrinology · Department of Pediatrics

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