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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
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  		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
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 References
 

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