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Editorial: Growth Inhibition by Insulin-Like Growth Factor (IGF) Binding Protein-3—What’s IGF Got To Do with It?

Molecular and Cellular Endocrinology Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Matthew M. Rechler, National Institutes of Health, Building 10, Room 8D-14, 10 Center Drive, MSC 1758, Bethesda, Maryland 20892-1758. E-mail: mrechler{at}helix.nih.gov

	Introduction

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Life has suddenly become more interesting for the insulin-like growth factor binding proteins (IGFBPs). For years the IGFBPs were relegated to preventing IGF-I or IGF-II from binding to IGF-I receptors and activating the signaling pathways that stimulated cell proliferation or survival (1, 2). They did this job well because they bound IGFs with higher affinity than did the receptors, forming inactive complexes that could not bind to the IGF-I receptor. First came the suggestion that they could potentiate IGF action, albeit only under precisely defined in vitro conditions (2). Now, recent studies with IGFBP-3, the most abundant IGFBP in the circulation, have opened new vistas for the proteins. Recent papers from several laboratories have reported that IGFBP-3 can: 1) inhibit growth without binding IGF-I and blocking its access to the IGF-I receptor; 2) travel to the cell nucleus instead of remaining outside the cell like a pariah; 3) induce apoptosis; and 4) mediate the potent growth inhibitory actions of transforming growth factor- (TGF-) ß and possibly the induction of apoptosis by the tumor suppressor, p53. And if this were not enough, new cousins (IGFBPs 7–10) have been discovered. These are heady times, indeed.

There were earlier premonitions that IGFBP-3 might have a secret life as an inhibitor of cell proliferation independent of IGFs and IGF-I receptors by a mechanism that did not involve sequestering IGF-I. Liu et al. (3) reported that rat IGFBP-3 inhibited the stimulation of chick embryo fibroblast (CEF) DNA synthesis by a serum fraction from which IGFs had been removed by acid gel-filtration. But the skeptics countered that other growth factors in serum might have stimulated the synthesis of endogenous IGFs, so that sequestration remained a possibility. Support came from Oh et al. (4), who showed that exogenous IGFBP-3 inhibited constitutively activated DNA synthesis in a human breast cancer cell line, and from Cohen et al. (5), who demonstrated that stable transfection of Balb c/3T3 mouse fibroblasts with human IGFBP-3 complementary DNA (cDNA) decreased the rate of cell proliferation. The key to the latter experiment was that addition of insulin, which has mitogenic activity in these cells but does not bind to and therefore can not be inhibited by IGFBP-3, could not overcome the decrease in cell proliferation. Still another blow to the skeptics came when Lalou et al. (6) showed that a 16-kDa fragment of IGFBP-3, generated by limited proteolysis of human recombinant IGFBP-3 with plasmin, inhibited IGF-I- and insulin-stimulated DNA synthesis in CEFs. Although both peptides act through the IGF-I receptor, the critical point is that the 16-kDa IGFBP-3 fragment has negligible binding affinity for IGF-I and presumably does not bind insulin, so that sequestration of the growth peptides was unlikely to explain the inhibition of cell proliferation.

The best was yet to come. Studies using a fibroblast cell line developed from mice with a targeted disruption of the IGF-I receptor (R^- cells) (7) established that the growth inhibitory effects of IGFBP-3 did not involve IGF binding to the IGF-I receptor. First, Valentinis et al. (8) reported that stable transfection of human IGFBP-3 cDNA slowed the proliferation of R^- cells, as it had in Balb c/3T3 fibroblasts. And in the present issue, Zadeh and Binoux (9) demonstrate that the 16-kDa IGFBP-3 fragment inhibited the stimulation of DNA synthesis in R^- cells by basic fibroblast growth factor (bFGF). Even if bFGF induced IGF-I synthesis in these experiments, the IGF-I could not have stimulated DNA synthesis through the IGF-I receptor. (Only a diehard skeptic would suggest that IGF-I still might act through another receptor pathway, such as the insulin receptor).

If IGFBP-3 is not acting by simply preventing IGF-I from binding to the IGF-I receptor, how does it inhibit growth? The final answer is not in, but some important clues are available. First, it has been appreciated for several years that IGFBP-3 associates with different cells and that this binding was decreased by incubation with heparin (10, 11). Although these experiments were initially interpreted as indicating that heparin competitively inhibited the binding of IGFBP-3 to a cell-associated heparan sulfate proteoglycan, this does not appear to be the case because complete enzymatic removal of heparan sulfate and other glycosaminoglycans from the cell surface did not affect IGFBP-3 binding (12). An alternative explanation, that the binding of heparin to IGFBP-3 induced a conformational change in the protein that decreased its ability to bind to putative IGFBP-3 receptors on the cell surface, was proposed. A heparin binding domain (XBBBXXBX, where B is a basic amino acid and X is a nonbasic amino acid) is present in a highly basic region (residues 214–232) in the COOH-terminal portion of IGFBP-3.

Identification of the putative IGFBP-3 receptors remains elusive. Although several cell-associated proteins that bind IGFBP-3 have been described (13, 14, 15), the specificity of the binding and whether these IGFBP-3-binding proteins have a functional role in growth inhibition by IGFBP-3 must be established before they can be considered signaling IGFBP-3 receptors. Nonetheless, the ability of IGFBP-3 to bind to cells is strongly correlated with its ability to cause growth inhibition, suggesting that IGFBP-3 must interact with specific cell receptors before growth inhibition can occur. The strongest evidence for this hypothesis comes from the concomitant effects of IGF-I on cell-surface binding of IGFBP-3 and on IGFBP-3-induced growth inhibition. IGF-I blocks the association of IGFBP-3 with cells (10, 11, 12, 16), and IGF-I (but not IGF-I analogues that can bind to the IGF-I receptor but not to IGFBP-3) reverses the IGFBP-3-induced inhibition of Hs578T breast cancer cell growth (4). In other words, the ability of IGF-I to overcome the growth inhibitory effects of IGFBP-3 depends on its ability to bind to IGFBP-3, not its ability to bind to the IGF-I receptor. Because IGFBP-3 can bind to cells, but IGF-I:IGFBP-3 complexes cannot, this result supports the hypothesis that interaction of IGFBP-3 with specific cell receptors is required for growth inhibition. Possibly IGF-I, like heparin, induces a conformational change in IGFBP-3 that prevents it from binding to the IGF-I receptor (12).

The basic region of the COOH-terminal segment of IGFBP-3 also contains a bipartite nuclear localization signal, and nuclear localization of IGFBP-3 has been reported in two recent papers (17, 18). Jaques et al. (17) identified IGFBP-3 by immunostaining in the nucleus and cytoplasm of nonsmall cell lung carcinoma cells. Li et al. (18) showed in proliferating opossum kidney cells that fluorescent IGFBP-3 and IGF-I, added separately or together, were taken up from the media and colocalized in the nucleus. This provocative study suggests that IGFBP-3 may transport IGF-I to the nucleus and raises the additional possibility that nuclear IGFBP-3 may regulate the transcription of critical growth inhibitory genes independent of IGF-I. Whether nuclear localization of IGFBP-3 can occur by intracrine as well as secretion-reuptake pathways remains to be determined.

Although these sites in the COOH-terminal portion of IGFBP-3 represent potential growth inhibitory domains in systems in which intact IGFBP-3 appears to be the active growth inhibitory species (4), they do not account for the inhibition of insulin-stimulated DNA synthesis in CEFs or bFGF-stimulated DNA synthesis in R^- cells by the 16-kDa IGFBP-3 fragment (6, 9). Lalou et al. (19) recently reported that this fragment corresponds to the NH₂-terminal residues 1–92. As intact IGFBP-3 did not inhibit growth in their studies (6, 9), these results suggest that the inhibitory domain located in the NH₂-terminus may not be accessible in the intact molecule.

Induction of apoptosis appears to be a major component of IGF-independent growth inhibition. Recently, Rajah et al. (15) reported that exogenous IGFBP-3 induced programmed cell death in PC-3 human prostate carcinoma cells and in mouse fibroblasts. The induction of PC-3 cell apoptosis by IGFBP-3 was reversed by IGF-I but not by an IGF-I analogue that does not bind to IGFBP-3, reminiscent of their abilities to reverse the growth inhibitory effects of IGFBP-3 seen in breast cancer cells, suggesting that apoptosis was induced by IGFBP-3 but not by IGF-I: IGFBP-3 complexes. Increased apoptosis in R^- cells that had been stably transfected with IGFBP-3 cDNA indicates that a functional IGF-I receptor is not required for the induction of apoptosis. Incubation with IGF-I or antibodies to IGFBP-3 partially decreased the observed apoptosis, suggesting that secretion-reuptake and possibly intracrine pathways are involved.

Interest in the growth inhibitory activity of IGFBP-3 intensified when it was appreciated that some of the most potent inhibitors of cell growth increased IGFBP-3 expression, raising the possibility that IGFBP-3 mediated the effects of these agents on cell proliferation and apoptosis. TGF-ß (15, 20), retinoic acid (21), antiestrogens (22), and the tumor suppressor p53 (23) all induce IGFBP-3. The growth inhibitory effects of TGF-ß, retinoic acid, and antiestrogens in human breast cancer cells (20, 21, 22), and the induction of apoptosis by TGF-ß in PC-3 cells (15), appear to be mediated, at least in part, by IGFBP-3, as convincingly demonstrated in experiments using antisense oligonucleotides to IGFBP-3. Moreover, growth inhibition by TGF-ß in breast cancer cells (20), and the induction of apoptosis by TGF-ß in prostate cancer cells (15), appears to be IGF- and IGF-I-receptor-independent, but IGF-independence has not yet been established for antiestrogens or retinoic acid. Increased expression of IGFBP-3 is correlated with the ability of p53 mutants to induce apoptosis (23, 24, 25), but it has yet to be established that IGFBP-3 mediates p53-induced apoptosis.

More surprises are surely in store. After a 6-yr hiatus, membership in the IGFBP superfamily has increased from its six charter members (IGFBPs 1–6) to at least ten [(26); Y. Oh, personal communication]. IGFBPs 7–10 have low affinity for IGFs and promise to provide new insights into IGF-independent IGFBP signaling pathways. And IGF-independent actions of IGFBPs need not be inhibitory, as evidenced by the ability of IGFBP-1 to stimulate cell migration by interacting with the fibronectin receptor (2). Clearly, there is more to IGFBPs than binding IGFs.

Received May 8, 1997.

	References

Top Introduction References

 

1. Rechler MM 1993 Insulin-like growth factor binding proteins. Vitam Horm 47:1–114[Medline]
2. Jones JI, Clemmons DR 1995 Insulin-like growth factors and their binding proteins: Biological actions. Endocr Rev 16:3–34[CrossRef][Medline]
3. Liu L, Delbé J, Blat C, Zapf J, Harel L 1992 Insulin-like growth factor binding protein (IGFBP-3), an inhibitor of serum growth factors other than IGF-I and -II. J Cell Physiol 153:15–21[CrossRef][Medline]
4. Oh Y, Müller HL, Lamson G, Rosenfeld RG 1993 Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells. J Biol Chem 268:14964–14971[Abstract/Free Full Text]
5. Cohen P, Lamson G, Okajima T, Rosenfeld RG 1993 Transfection of the human insulin-like growth factor binding protein-3 gene into Balb/c fibroblasts inhibits cellular growth. Mol Endocrinol 7:380–386[Abstract]
6. Lalou C, Lassarre C, Binoux M 1996 A proteolytic fragment of insulin-like growth factor (IGF) binding protein-3 that fails to bind IGFs inhibits the mitogenic effects of IGF-I and insulin. Endocrinology 137:3206–3212[Abstract]
7. Sell C, Rubini M, Rubin R, Liu J-P, Efstratiadis A, Baserga R 1993 Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci USA 90:11217–11221[Abstract/Free Full Text]
8. Valentinis B, Bhala A, DeAngelis T, Baserga R, Cohen P 1995 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 9:361–367[Abstract]
9. Zadeh SM, Binoux M 1997 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 138:3069–3072[Abstract/Free Full Text]
10. Martin JL, Ballesteros M, Baxter RC 1992 Insulin-like growth factor-I (IGF-I) and transforming growth factor-ß1 release IGF-binding protein-3 from human fibroblasts by different mechanisms. Endocrinology 131:1703–1710[Abstract]
11. Smith EP, Lu L, Chernausek SD, Klein DJ 1994 Insulin-like growth factor-binding protein-3 (IGFBP-3) concentration in rat Sertoli cell-conditioned medium is regulated by a pathway involving association of IGFBP-3 with cell surface proteoglycans. Endocrinology 135:359–364[Abstract]
12. Yang YW-H, Yanagishita M, Rechler MM 1996 Heparin inhibition of insulin-like growth factor binding protein-3 (IGFBP-3) binding to human fibroblasts and rat glioma cells: role of heparan sulfate proteoglycans. Endocrinology 137:4363–4371[Abstract]
13. Oh Y, Müller 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]
14. Hodgkinson S, Fowke P, Al Somai N, McQuoid M 1995 Proteins in tissue extracts which bind insulin-like growth factor binding protein-3 (IGFBP-3). J Endocrinol 145:R1–R6
15. Rajah R, Valentinis B, Cohen P 1997 Insulin-like growth factor-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]
16. Oh Y, Müller HL, Pham H, Lamson G, Rosenfeld RG 1992 Non-receptor mediated, post-transcriptional regulation of insulin-like growth factor binding protein (IGFBP)-3 in Hs578T human breast cancer cells. Endocrinology 131:3123–3125[Abstract]
17. Jaques G, Noll K, Wegmann B, Witten S, Kogan E, Radulescu RT, Havemann K 1997 Nuclear localization of insulin-like growth factor binding protein 3 in a lung cancer cell line. Endocrinology 138:1767–1770[Abstract/Free Full Text]
18. Noll K, Wegmann B, Havemann K, Jaques G 1996 Insulin-like growth factors stimulate the release of insulin-like growth factor-binding protein-3 (IGFBP-3) and degradation of IGFBP-4 in nonsmall cell lung cancer cell lines. J Clin Endocrinol Metab 81:2653–2662[Abstract]
19. Lalou C, Sawamura S, Segovia B, Ogawa Y, Binoux M Proteolytic fragments of insulin-like growth factor binding protein-3:N-terminal sequences and relationships between structure and biological activity. Comptes Rendues Acad Sci Paris, Life Sciences, in press
20. Oh Y, Müller HL, Ng L, Rosenfeld RG 1995 Transforming growth factor-ß-induced cell growth inhibition in human breast cancer cells is mediated through insulin-like growth factor-binding protein-3 action. J Biol Chem 270:13589–13592[Abstract/Free Full Text]
21. Gucev ZS, Oh Y, Kelley KM, Rosenfeld RG 1996 Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor ß2-induced growth inhibition in human breast cancer cells. Cancer Res 56:1545–1550[Abstract/Free Full Text]
22. Huynh H, Yang XF, Pollak M 1996 Estradiol and antiestrogens regulate a growth inhibitory insulin-like growth factor binding protein 3 autocrine loop in human breast cancer cells. J Biol Chem 271:1016–1021[Abstract/Free Full Text]
23. 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]
24. Friedlander P, Haupt Y, Prives C, Oren M 1996 A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis. Mol Cell Biol 16:4961–4971[Abstract]
25. Ludwig RL, Bates S, Vousden KH 1996 Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol Cell Biol 16:4952–4960[Abstract]
26. Oh Y, Nagalla SR, Yamanaka Y, Kim H-S, Wilson E, Rosenfeld RG 1996 Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. J Biol Chem 271:30322–30325[Abstract/Free Full Text]

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