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Insulin-like growth factor binding protein-3 has dual effects on gastrointestinal stromal tumor cell viability and sensitivity to the anti-tumor effects of imatinib mesylate in vitro

Jheri J Dupart15, Jonathan C Trent25, Ho-Young Lee35, Kenneth R Hess45, Andrew K Godwin6, Takahiro Taguchi7 and Wei Zhang15*

Author Affiliations

1 Department of Pathology, the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

2 Department of Sarcoma Medical Oncology, the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

3 Department of Head and Neck Thoracic Oncology, the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

4 Department of Biostatistics, the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

5 Graduate School of Biomedical Sciences, the University of Texas Health Science Center at Houston, Houston, Texas, USA

6 Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

7 Department of Human Health and Medical Science, Kochi University, Nankoku, Kochi, Japan

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Molecular Cancer 2009, 8:99  doi:10.1186/1476-4598-8-99

Published: 10 November 2009

Abstract

Background

Imatinib mesylate has significantly improved survival and quality of life of patients with gastrointestinal stromal tumors (GISTs). However, the molecular mechanism through which imatinib exerts its anti-tumor effects is not clear. Previously, we found up-regulation of insulin-like growth factor binding protein-3 (IGFBP3) expression in imatinib-responsive GIST cells and tumor samples. Because IGFBP3 regulates cell proliferation and survival and mediates the anti-tumor effects of a number of anti-cancer agents through both IGF-dependent and IGF-independent mechanisms, we hypothesized that IGFBP3 mediates GIST cell response to imatinib. To test this hypothesis, we manipulated IGFBP3 levels in two imatinib-responsive GIST cell lines and observed cell viability after drug treatment.

Results

In the GIST882 cell line, imatinib treatment induced endogenous IGFBP3 expression, and IGFBP3 down-modulation by neutralization or RNA interference resulted in partial resistance to imatinib. In contrast, IGFBP3 overexpression in GIST-T1, which had no detectable endogenous IGFBP3 expression after imatinib, had no effect on imatinib-induced loss of viability. Furthermore, both the loss of IGFBP3 in GIST882 cells and the overexpression of IGFBP3 in GIST-T1 cells was cytotoxic, demonstrating that IGFBP3 has opposing effects on GIST cell viability.

Conclusion

This data demonstrates that IGFBP3 has dual, opposing roles in modulating GIST cell viability and response to imatinib in vitro. These preliminary findings suggest that there may be some clinical benefits to IGFBP3 therapy in GIST patients, but further studies are needed to better characterize the functions of IGFBP3 in GIST.