Customizing the Targeting of IGF-1 Receptor

Renato Baserga


Future Oncol. 2009;5(1):43-50. 

In This Article

Role of IRS-1

The various properties of IRS-1 are summarized in Box 2. IRS-1 plays a significant role in cell size, cell proliferation and transformation.[17] Although IRS-1 was originally named as a substrate of the InR, it turns out that it is the IGF-IR that is its main activator. This is best illustrated by the so-called IRS-1 paradox (Figure 1). Deletion of the IGF-IR in mouse embryos results in newborn mice that are approximately 50% normal size.[1] Deletion of IRS-1 also results in mouse embryos that are 50% in size,[18] and one would expect that deletion of the InR would do the same. Instead, mice with a deletion of the InR at birth are normal in size.[1] Body size (which is based on both cell size and cell number) depends much more on IGF-IR/IRS-1 signaling than on the InR. An explanation of the paradox may be due to the fact that the activated IGF-IR is much more powerful than the activated InR in causing nuclear translocation of IRS-1.[7] In the nucleus, IRS-1 binds and activates the upstream binding factor-1, a cofactor that increases the transcriptional activity of RNA polymerase I.[19] Incidentally, binding of IRS-1 to the upstream binding factor-1 provides a molecular explanation for the effect of IRS-1 on cell and body size, which largely depend on rRNA synthesis.

Figure 1.

The insulin receptor substrate paradox. IGF-IR = Type 1 IGF receptor; IRS-1 = Insulin receptor substrate-1.

IRS-1 in Cancer

IRS-1 has been proposed as a biomarker for cancer.[20] IRS-1 expression is increased in human tumors[21] and overexpression of IRS-1 causes cell transformation, including the ability to form colonies in soft agar, and tumors and metastases in mice.[12,13,22,23,24,25,26] IRS-1 is required for transformation by the simian virus 40 T antigen[27] or v-src.[28] Conversely, downregulation of IRS-1 (by antisense or siRNA procedures) reverses the transformed phenotype.[28,29,30,31] IRS-1 is especially effective in inducing cell proliferation when it translocates to nuclei (see above). The ability of IRS-1 to cause cell transformation, and the tendency to lose the transformed phenotype in cells in which IRS-1 is low or has been downregulated, suggest that the importance of the IGF-IR in cancer may be dependent on IRS-1 as much as on the receptor itself. When IRS-1 is activated directly, for instance by v-src, the IGF-IR is no longer a requirement for transformation.[28]


IRS-2 (highly homologous to IRS-1 in the pleckstrin- and phosphotyrosine-binding domains) undoubtedly transmits an IGF-IR signal. Its role in cell proliferation is ambiguous. I lean toward an IRS-2 that sends a signal, but not a mitogenic one. This is an opinion based on two experiments. The first is by Bruning et al.,[32] who used mouse embryo fibroblasts with a deletion of the IRS-1 genes. The cells responded to IGF-1 normally, except for cell proliferation; not even overexpression of IRS-2 caused IGF-I to be mitogenic in these cells. The second experiment is by Shi et al.,[33] who targeted IRS-1 with a microRNA (microRNA 145) that downregulates IRS-1 but not IRS-2 (different 3'-UTR). MicroRNA 145 dramatically inhibited the growth of colon cancer cells, despite the presence of IRS-2.

The Experiment of Doug Yee

The suggestion of an important role of IRS-1 in cancer therapy is supported by the report of Byron et al.,[5] which showed that an antibody to the IGF-IR is ineffective on T47D-YA breast cancer cells unless IRS-1 and IRS-2 are expressed. This finding has not received the attention it deserves. It is not just a pointer to IRS proteins as biomarkers for IGF-IR targeting, but it also has profound implications. A superficial explanation of the finding of Yee and his collaborators is simple. Without IRS-1, the IGF-IR does not send a mitogenic signal, but a differentiation signal (see above). An antibody to the receptor will therefore have no effect on the growth of T47D-YA cells that do not express IRS-1. It may even have an undesirable effect, as an antibody to the IGF-IR would actually inhibit any differentiation (growth arrest) signal originating from IGF-1.[34] However, there is a more important implication in the findings of Byron et al.[5] Parental T47D-YA cells are growing presumably using other growth factors in serum, totally indifferent to the presence of IGFs since the IGF-IR is not mitogenic in the absence of IRS-1. However, as soon as IRS proteins are introduced, the cells become sensitive to an IGF-IR antibody, as if the presence of IRS-1 had switched the cells to IGF-1 dependence. This is an example of an acquired taste for IGF-I, that is, the ability of cells to switch to another growth factor when the situation changes. As previously mentioned, there are several reports in the literature that tumor cells can switch from the EGFR to the IGF-IR (and vice versa) when the tumors are treated with respective antibodies. This ability to switch is probably more frequent than it is generally believed. In Yee's case, it was due to an intracellular change. In the next example it is an environmental change that seems to switch the allegiance of tumor cells to IGF-1.


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