Original Article

Journal of Gastrointestinal Surgery

, Volume 15, Issue 6, pp 942-957

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

  • Li YangAffiliated withDepartment of Oncology, Southwest Hospital, Third Military Medical UniversityDepartment of Oncology, Guizhou Cancer Hospital, Guiyang Medical College
  • , Jianjun LiAffiliated withDepartment of Oncology, Southwest Hospital, Third Military Medical University
  • , Li RanAffiliated withDepartment of Oncology, Guizhou Cancer Hospital, Guiyang Medical College
  • , Feng PanAffiliated withDepartment of Oncology, Southwest Hospital, Third Military Medical University
  • , Xiaoxin ZhaoAffiliated withDepartment of Oncology, Southwest Hospital, Third Military Medical University
  • , Zhenyu DingAffiliated withDepartment of Oncology, Southwest Hospital, Third Military Medical University
  • , Yuying ChenAffiliated withDepartment of Oncology, Southwest Hospital, Third Military Medical University
  • , Qiuping PengAffiliated withDepartment of Oncology, 94th Hospital
  • , Houjie LiangAffiliated withDepartment of Oncology, Southwest Hospital, Third Military Medical University Email author 

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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.

Keywords

Colorectal cancer Epidermal growth factor receptor Gefitinib Insulin-like growth factor receptor-1β Phosphorylation