help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cohen, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cohen, P.
Endocrinology Vol. 147, No. 5 2109-2111
Copyright © 2006 by The Endocrine Society

Insulin-Like Growth Factor Binding Protein-3: Insulin-Like Growth Factor Independence Comes of Age

Pinchas Cohen

Division of Pediatric Endocrinology Mattel Children’s Hospital Department of Pediatrics David Geffen School of Medicine University of California, Los Angeles Los Angeles, California 90095

Address all correspondence and requests for reprints to: Pinchas Cohen, M.D., Professor and Chief, Division of Pediatric Endocrinology, Mattel Children’s Hospital, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095. E-mail: hassy{at}mednet.ucla.edu.

IGF binding protein-3 (IGFBP-3) is a multifunctional protein that induces apoptosis using both IGF-dependent and -independent mechanisms. The IGF-independent effects of IGFBP-3 are mediated through binding to matrix, cell-surface, cytoplasmic, nuclear, and mitochondrial molecules. IGFBP-3 modulates signaling via nuclear receptors such as retinoid X receptor and regulates both the intrinsic and extrinsic apoptosis pathways. Although the IGF-independent actions of IGFBP-3 have been demonstrated extensively using in vitro cellular models, only recently has evidence emerged supporting a role for the IGF-independent actions of IGFBP-3 in vivo. Using transgenic mice and other models, it is evident that IGFBP-3 inhibits systemic IGF-mediated growth and antagonizes insulin action but has no clear adverse effects on the survival of benign cells. Remarkably, IGFBP-3 potently inhibits the progression of malignant tumors in transgenic mice by promoting apoptosis of cancer cells. Using IGFBP-3 mutants that do not bind IGF-I, it was demonstrated that this effect is both IGF inhibitory and IGF independent.

IGFBP-3 has been recognized as a growth inhibitory, proapoptotic molecule for over a decade (1). IGF-independent mechanisms were proposed as central to the action of IGFBP-3 even before any pathways for these actions had been identified (2). Study of the IGF-independent actions of IGFBP-3 relied on several experimental tools. First, demonstrating that growth and survival induced by IGF analogs that fail to bind IGFBPs are nonetheless inhibited by IGFBP-3 strongly supported IGF independence (3). Second, the action of IGFBP-3 on cells that lack the type-1 IGF receptor argued for an alternative pathway for its actions (4). Third, the recognition of IGFBP-3 association with potential receptors, initially identified at the cell surface, represented a likely explanation for the IGF-independent effects (5). However, the mechanism for the IGF-independent actions of IGFBP-3 has grown to be far more complicated than the classical ligand-receptor-signaling paradigm under which most growth factors operate. In the last 5 yr, over a dozen molecules have been shown to bind IGFBP-3 with high affinity and functional significance (6) and this list is still growing. Finally, and perhaps most important, the development of IGFBP-3 analogs that fail to bind IGFs proved to be the most critical tool for the unraveling of the IGF-independent actions of IGFBP-3 (7, 8, 9). These mutants have been shown to retain many of the activities of IGFBP-3 on apoptosis induction in vitro (10). In a landmark paper establishing a role for the IGF-independent actions of IGFBP-3 on in vivo tumor formation, Silha et al. (11) capitalized on this tool by mating a prostate cancer mouse model expressing the large simian virus 40 T antigen driven by the probasin promotor with a pair of transgenic mice strains expressing either hIGFBP-3 or the GGG-IGFBP-3 mutant, which is non-IGF binding. In a previous paper by this group describing the GGG-IGFBP-3-overexpressing mouse, there was a surprising lack of any dramatic phenotype, especially one involving growth (12), whereas the wild-type IGFBP-3 transgenic mice exhibited growth retardation (13), abnormal bone formation (14), and glucose intolerance (15). Indeed, this illustrates the importance of IGFs in normal physiology and the critical role IGFBP-3 plays as an IGF-inhibitory factor, but it was perplexing to observe the apparent absence of IGF-independent effects, a fact that was possibly attributable to the relatively low levels of the IGFBP-3 mutant measured in the circulation of the mice, secondary to the rapid clearance of the GGG-IGFBP-3 that fails to form the ternary complex with IGFs and acid-labile subunit. However, the emerging paradigm is that IGFBP-3 acts as a modulator of IGF action on normal somatic growth but participates in the regulation of tumor cell survival as an IGF-independent entity.

IGFBP-3 has demonstrated an expanding significance in cancer. Epidemiological studies have shown IGFBP-3 to be protective against prostate cancer and other malignancies (16), and multiple studies of cancer cell biology (17) and human genetics (18) indicate that it is important in the evolution of malignancies. Close examination of the data by Silha et al., as well as findings in epidemiological studies examining the relationship between circulating IGFBP-3 levels and cancer risk, suggest that tissue levels of IGFBP-3, rather than serum levels, have the largest impact on tumor development.

The data of Silha et al. indicating that overexpression of IGFBP-3, but not GGG-IGFBP-3, in prostate tumors dramatically suppresses the development at murine tumors at 12 wk (the equivalent of prostatic intraepithelial neoplasia, or PIN, in the human) indicates an important role for the IGF-dependent actions of IGFBP-3 on cancer prevention and, by extension, a central role for IGFs in the etiology of this disease. This is compatible with a number of papers that described an exclusively IGF-dependent effect of IGFBP-3 on certain cancer models (19). Interestingly, circulating IGF-I levels were higher in the transgenic IGFBP-3 mice, suggesting that local rather than systemic IGF is the culprit. On the other hand, in mice examined at 17 and 21 wk (the equivalent of locally invasive to advanced disease in the human), tumors were equally (and potently) suppressed by the presence of IGFBP-3 and the non-IGF-binding mutant GGG-IGFBP-3. This indicates that during later events in the evolution of the cancer, when angiogenesis, invasion, and overcoming apoptosis are critical for the tumor, IGFBP-3 is an important tumor-suppressor acting entirely through an IGF-independent mechanism (Fig. 1Go). Indeed, several tumors are characterized by loss of IGFBP-3 expression as a result of promotor methylation (20). It is also remarkable that IGFBP-3 has such dramatic effects on tumor growth, reducing weight by 50% or more, but only minimal effects on the growth of normal organs. This may be an attractive feature in the potential development of IGFBP-3 as an anticancer agent.


Figure 1
View larger version (31K):
[in this window]
[in a new window]
  		FIG. 1. IGF-dependent and IGF-independent effects of IGFBP-3 on prostate cancer progression. Shown are the potential effects of IGFs and IGFBP-3 on the development of cancer (CA) in early and advanced stages.

 
Although an important and highly potent biological activity of IGFBP-3 in vivo as an IGF-independent molecule that suppresses tumor progression and induces apoptosis has been established, the actual mechanism for these IGF-independent effects remains poorly understood. IGFBP-3 binds to matrix molecules such as type-1 collagen and the latent TGFß binding protein-1 (21), as well as to cell surface receptors such as the low-density lipoprotein receptor-related protein-1 (22), and, via transferrin, uses the transferrin receptor and caveolin pathways for rapid internalization directly into the nucleus (23), possibly employing ß-importin binding to a nuclear localization signal peptide in its C-terminal region (24). Although IGFBP-3 can sometimes induce apoptosis through nonnuclear pathways (25), its interactions with the nuclear transcription factor retinoid X receptor appears to be essential to its actions in some models (26). IGFBP-3 has also been described to interact with mitochondrial apoptosis regulators such as Nur77 (27) and to inhibit the Bax-antagonist humanin (28). Furthermore, processing of intracellular IGFBP-3, for example by phosphorylation, may be critical for its actions (29).

What are the clinical implications of the recognition of these in vivo IGF-independent actions of IGFBP-3? This protein may have a role as a diagnostic tool in predicting the risk and the prognosis of prostate and other cancers, and its levels may represent the response of tumors to certain therapies. In fact, therapy with IGFBP-3 has recently been shown to suppress the growth of prostate cancer xenografts in severe combined immunodeficient mice (30), and IGFBP-3 may be involved in angiogenesis suppression (31, 32). Potential future therapies for cancer may include IGFBP-3 or one of its mutants, as well as agents that act as IGFBP-3 inducers, including dietary phytochemicals (33). Clearly, ongoing research will clarify the ideal clinical scenarios that may respond to: 1) blockade of IGF action; 2) activation of IGFBP-3-induced apoptosis in tumors; and 3) IGFBP-3 interaction with other emerging therapies for cancer.


   Footnotes
 
This work was supported in part by a Prostate Cancer Foundation award and National Institutes of Health Grants RO1AG20954, P50CA92131, and RO1CA100938.

Disclosure summary: The author has no conflict of interest to declare.

Abbreviation: IGFBP-3, IGF binding protein-3.

Received February 15, 2006.

Accepted for publication February 23, 2006.


   References
Top
 References
 

  1. Rajah R, Valentinis B, Cohen P 1997 Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-ß1 on programmed cell death through a p53- and IGF-independent mechanism. J Biol Chem 272:12181–12188[Abstract/Free Full Text]
  2. Cohen P, Lamson G, Okajima T, Rosenfeld RG 1993 Transfection of the human IGF binding protein-3 gene into Balb/c fibroblasts inhibits cellular growth. Mol Endocrinol 7:380–386[Abstract/Free Full Text]
  3. Oh Y, Muller HL, Lamson G, Rosenfeld RG 1993 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 268:14964–14971[Abstract/Free Full Text]
  4. Valentinis B, Bhala A, Baserga R, Cohen P 1995 Transfection of the human insulin-like growth factor (IGF) binding protein-3 gene into fibroblasts from IGF-receptor gene-targeted mice inhibits cellular growth. Mol Endocrinol 9:361–367[Abstract/Free Full Text]
  5. Oh Y, Muller HL, Pham H, Rosenfeld RG 1993 Demonstration of receptors for insulin-like growth factor binding protein-3 on Hs578T human breast cancer cells. J Biol Chem 268:26045–26048[Abstract/Free Full Text]
  6. Firth SM, Baxter RC 2002 Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824–854[Abstract/Free Full Text]
  7. Buckway CK, Wilson EM, Ahlsen M, Bang P, Oh Y, Rosenfeld RG 2001 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 86:4943–4950[Abstract/Free Full Text]
  8. Hong J, Zhang G, Dong F, Rechler MM 2002 Insulin-like growth factor (IGF)-binding protein-3 mutants that do not bind IGF-I or IGF-II stimulate apoptosis in human prostate cancer cells. J Biol Chem 277:10489–10497[Abstract/Free Full Text]
  9. Perks CM, McCaig C, Clarke JB, Clemmons DR, Holly JM 2002 A non-IGF binding mutant of IGFBP-3 modulates cell function in breast epithelial cells. Biochem Biophys Res Commun 294:988–994[CrossRef][Medline]
  10. Longobardi L, Torello M, Buckway C, O’Rear L, Horton WA, Hwa V, Roberts CT Jr., Chiarelli F, Rosenfeld RG, Spagnoli A 2003 A novel insulin-like growth factor (IGF)-independent role for IGF binding protein-3 in mesenchymal chondroprogenitor cell apoptosis. Endocrinology 144:1695–1702[Abstract/Free Full Text]
  11. Silha JV, Sheppard PC, Mishra S, Gui Y, Schwartz J, Dodd JG, Murphy LJ 2006 Insulin-like growth factor (IGF) binding protein-3 attenuates prostate tumor growth by IGF-dependent and IGF-independent mechanisms. Endocrinology 147:2112–2121[Abstract/Free Full Text]
  12. Silha JV, Gui Y, Mishra S, Leckstrom A, Cohen P, Murphy LJ 2005 Overexpression of Gly56/Gly80/Gly81-mutant IGFBP-3 in transgenic mice. Endocrinology 146:1523–1531[Abstract/Free Full Text]
  13. Modric T, Silha JV, Shi Z, Gui Y, Suwanichkul A, Durham SK, Powell DR, Murphy LJ 2001 Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice. Endocrinology 142:1958–1967[Abstract/Free Full Text]
  14. Silha JV, Mishra S, Rosen CJ, Beamer WG, Turner RT, Powell DR, Murphy LJ 2003 Perturbations in bone formation and resorption in insulin-like growth factor binding protein-3 transgenic mice. J Bone Miner Res 18:1834–1841[CrossRef][Medline]
  15. Silha JV, Gui Y, Murphy LJ 2002 Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice. Am J Physiol Endocrinol Metab 283:E937–E945
  16. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M 1998 Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279:563–566[Abstract/Free Full Text]
  17. Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, Kley N 1995 Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377:646–649[CrossRef][Medline]
  18. Le Marchand L, Kolonel LN, Henderson BE, Wilkens LR 2005 Association of an exon 1 polymorphism in the IGFBP3 gene with circulating IGFBP-3 levels and colorectal cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 14:1319–1321[Abstract/Free Full Text]
  19. Takaoka M, Smith CE, Mashiba MK, Okawa T, Andl CD, El-Deiry WS, 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
  20. Chang YS, Wang L, Suh YA, Mao L, Karpen SJ, Khuri FR, Hong WK, Lee HY 2004 Mechanisms underlying lack of insulin-like growth factor-binding protein-3 expression in non-small-cell lung cancer. Oncogene 23:6569–6580[CrossRef][Medline]
  21. Gui Y, Murphy LJ 2003 Interaction of insulin-like growth factor binding protein-3 with latent transforming growth factor-ß binding protein-1. Mol Cell Biochem 250:189–195[CrossRef][Medline]
  22. Huang SS, Ling TY, Tseng WF, Huang YH, Tang FM, Leal SM, Huang JS 2003 Cellular growth inhibition by IGFBP-3 and TGF-ß1 requires LRP-1. FASEB J 17:2068–2081[Abstract/Free Full Text]
  23. Lee KW, Liu B, Ma L, Li H, Bang P, Koeffler HP, Cohen P 2004 Cellular internalization of insulin-like growth factor binding protein-3 (IGFBP-3): distinct endocytic pathways facilitate reuptake and nuclear localization. J Biol Chem 279:469–476[Abstract/Free Full Text]
  24. Schedlich LJ, Le Page SL, Firth SM, Briggs LJ, Jans DA, Baxter RC 2000 Nuclear import of insulin-like growth factor-binding protein-3 and -5 is mediated by the importin ß subunit. J Biol Chem 275:23462–23470[Abstract/Free Full Text]
  25. Butt AJ, Fraley KA, Firth SM, Baxter RC 2002 IGF-binding protein-3-induced growth inhibition and apoptosis do not require cell surface binding and nuclear translocation in human breast cancer cells. Endocrinology 143:2693–2699[Abstract/Free Full Text]
  26. Liu B, Lee HY, Weinzimer SA, Powell DR, Clifford JL, Kurie JM, Cohen P 2000 Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-{alpha} regulate transcriptional signaling and apoptosis. J Biol Chem 275:33607–33613[Abstract/Free Full Text]
  27. Lee KW, Ma L, Yan X, Liu B, Zhang XK, Cohen P 2005 Rapid apoptosis induction by IGFBP-3 involves an IGF-independent nucleo-mitochondrial translocation of RXR{alpha}/Nur77. J Biol Chem 280:16942–16948[Abstract/Free Full Text]
  28. Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P 2003 Interaction between the Alzheimer’s survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci USA 2003 100:13042–13047[Abstract/Free Full Text]
  29. Schedlich LJ, Nilsen T, John AP, Jans DA, Baxter RC 2003 Phosphorylation of insulin-like growth factor binding protein-3 by deoxyribonucleic acid-dependent protein kinase reduces ligand binding and enhances nuclear accumulation. Endocrinology 144:1984–1993[Abstract/Free Full Text]
  30. Liu B, Lee KW, Li H, Ma L, Lin GL, Chandraratna RA, Cohen P 2005 Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo. Clin Cancer Res 11:4851–4856[Abstract/Free Full Text]
  31. Franklin SL, Ferry Jr RJ, Cohen P 2003 Rapid insulin-like growth factor (IGF)-independent effects of IGF binding protein-3 on endothelial cell survival. J Clin Endocrinol Metab 88:900–907[Abstract/Free Full Text]
  32. Oh SH, Kim WY, Kim JH, Younes MN, El-Naggar AK, Myers JN, Kies M, Cohen P, Khuri F, Hong WK, Lee HY 2006 Identification of IGFBP-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/Free Full Text]
  33. Singh RP, Sharma G, Mallikarjuna GU, Dhanalakshmi S, Agarwal C, Agarwal R 2004 In vivo suppression of hormone-refractory prostate cancer growth by inositol hexaphosphate: induction of insulin-like growth factor binding protein-3 and inhibition of vascular endothelial growth factor. Clin Cancer Res 10:244–250[CrossRef][Medline]



This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
Y. Jia, K.-W. Lee, R. Swerdloff, D. Hwang, L. J. Cobb, A. Sinha Hikim, Y. H. Lue, P. Cohen, and C. Wang
Interaction of Insulin-like Growth Factor-binding Protein-3 and BAX in Mitochondria Promotes Male Germ Cell Apoptosis
J. Biol. Chem., January 15, 2010; 285(3): 1726 - 1732.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
Y. Lue, R. Swerdloff, Q. Liu, H. Mehta, A. Sinha Hikim, K.-W. Lee, Y. Jia, D. Hwang, L. J. Cobb, P. Cohen, et al.
Opposing Roles of Insulin-Like Growth Factor Binding Protein 3 and Humanin in the Regulation of Testicular Germ Cell Apoptosis
Endocrinology, January 1, 2010; 151(1): 350 - 357.
[Abstract] [Full Text] [PDF]

Home page
 Anticancer ResHome page
S. RESSLER, J. RADHI, T. AIGNER, C. LOO, W. ZWERSCHKE, and C. SERGI
Insulin-like Growth Factor-binding Protein-3 in Osteosarcomas and Normal Bone Tissues
Anticancer Res, July 1, 2009; 29(7): 2579 - 2587.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
Y. Lue, C. Wang, Y. Cui, X. Wang, J. Sha, Z. Zhou, J. Xu, C. Wang, A. P. Sinha Hikim, and R. S. Swerdloff
Levonorgestrel Enhances Spermatogenesis Suppression by Testosterone with Greater Alteration in Testicular Gene Expression in Men
Biol Reprod, March 1, 2009; 80(3): 484 - 492.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. S. Fuchs, R. M. Goldberg, D. J. Sargent, J. A. Meyerhardt, B. M. Wolpin, E. M. Green, H. C. Pitot, and M. Pollak
Plasma Insulin-like Growth Factors, Insulin-like Binding Protein-3, and Outcome in Metastatic Colorectal Cancer: Results from Intergroup Trial N9741
Clin. Cancer Res., December 15, 2008; 14(24): 8263 - 8269.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
J. I-J. Leu and D. L. George
Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria
Genes & Dev., December 1, 2007; 21(23): 3095 - 3109.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
F. R. Santer, B. Moser, G. A. Spoden, P. Jansen-Durr, and W. Zwerschke
Human papillomavirus type 16 E7 oncoprotein inhibits apoptosis mediated by nuclear insulin-like growth factor-binding protein-3 by enhancing its ubiquitin/proteasome-dependent degradation
Carcinogenesis, December 1, 2007; 28(12): 2511 - 2520.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
L. Peng, P. J. Malloy, J. Wang, and D. Feldman
Growth Inhibitory Concentrations of Androgens Up-Regulate Insulin-Like Growth Factor Binding Protein-3 Expression via an Androgen Response Element in LNCaP Human Prostate Cancer Cells
Endocrinology, October 1, 2006; 147(10): 4599 - 4607.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cohen, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cohen, P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals