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Phosphorylated Insulin-Like Growth Factor 1 Receptor is Implicated in Resistance to the Cytostatic Effect of Gefitinib in Colorectal Cancer Cells

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Introduction

The ability of certain cancer cells to maintain signaling via the phosphoinositide-3-kinase/Akt and/or Ras/mitogen-activated protein kinase (MAPK) pathways has been repeatedly involved in resistance to epidermal growth factor receptor (EGFR) inhibition.

Discussion

We investigated the potential mechanisms of the uncoupling of EGFR from its downstream signals in colorectal cancer (CRC) cells. Alternative growth factor receptors and regulation of downstream pathways in different gefitinib-responsive cell lines were determined. Basal insulin-like growth factor receptor-1β (IGFR-1β) phosphorylation was undetectable or present at very low levels in highly gefitinib-responsive cell lines and was present at strikingly high levels in less responsive cell lines. Further analysis of cell lines representing the most sensitive (Lovo), moderately sensitive (HT29), and most resistant (HCT116) strains was treated with an IGFR-1 inhibitor (AG1024), gefitinib, or both, revealing that elevated IGFR-1β phosphorylation can compensate for the loss of EGFR signaling function. Increased insulin-like growth factor II expression induced by gefitinib or heterodimerization of EGFR and IGFR-1β may trigger IGFR-1β signal transduction via activation of Akt and MAPK. In addition, high levels of EGFR and IGFR-1β phosphorylation were detected in CRC tumor tissue. We also showed that gefitinib- and/or AG1024-induced cytostatic effects could be mediated by glycogen synthase kinase-3β (GSK-3β) activation. Our data suggest that the crosstalk between EGFR and IGFR-1β signaling are likely to contribute to resistance of CRC cells to gefitinib and that measurement of GSK-3β activation may present a potential biomarker for evaluating the antitumor efficacy of receptor tyrosine kinase inhibition.

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Acknowledgments

Gefitinib was generously provided by the AstraZeneca group of companies. This work was granted by Scientific Research Foundation of Third Military Medical University and supported by basic research program of EGFR targeted therapy operated by Wu Jieping Medical Fund (grant EGFR07-07).

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Authors and Affiliations

  1. Department of Oncology, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People’s Republic of China

    Li Yang, Jianjun Li, Feng Pan, Xiaoxin Zhao, Zhenyu Ding, Yuying Chen & Houjie Liang

  2. Department of Oncology, Guizhou Cancer Hospital, Guiyang Medical College, Guiyang, Guizhou, People’s Republic of China

    Li Yang & Li Ran

  3. Department of Oncology, 94th Hospital, Nanchang, Jiangxi, People’s Republic of China

    Qiuping Peng

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  1. Li Yang
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Correspondence to Houjie Liang.

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Li Yang and Jianjun Li contributed equally to this study.

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Yang, L., Li, J., Ran, L. et al. Phosphorylated Insulin-Like Growth Factor 1 Receptor is Implicated in Resistance to the Cytostatic Effect of Gefitinib in Colorectal Cancer Cells. J Gastrointest Surg 15, 942–957 (2011). https://doi.org/10.1007/s11605-011-1504-z

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