PMID- 21479670 OWN - NLM STAT- MEDLINE DCOM- 20111019 LR - 20240213 IS - 1873-4626 (Electronic) IS - 1091-255X (Linking) VI - 15 IP - 6 DP - 2011 Jun TI - Phosphorylated insulin-like growth factor 1 receptor is implicated in resistance to the cytostatic effect of gefitinib in colorectal cancer cells. PG - 942-57 LID - 10.1007/s11605-011-1504-z [doi] AB - 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-1beta (IGFR-1beta) 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-1beta 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-1beta may trigger IGFR-1beta signal transduction via activation of Akt and MAPK. In addition, high levels of EGFR and IGFR-1beta 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-3beta (GSK-3beta) activation. Our data suggest that the crosstalk between EGFR and IGFR-1beta signaling are likely to contribute to resistance of CRC cells to gefitinib and that measurement of GSK-3beta activation may present a potential biomarker for evaluating the antitumor efficacy of receptor tyrosine kinase inhibition. FAU - Yang, Li AU - Yang L AD - Department of Oncology, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China. FAU - Li, Jianjun AU - Li J FAU - Ran, Li AU - Ran L FAU - Pan, Feng AU - Pan F FAU - Zhao, Xiaoxin AU - Zhao X FAU - Ding, Zhenyu AU - Ding Z FAU - Chen, Yuying AU - Chen Y FAU - Peng, Qiuping AU - Peng Q FAU - Liang, Houjie AU - Liang H LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20110409 PL - Netherlands TA - J Gastrointest Surg JT - Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract JID - 9706084 RN - 0 (Antineoplastic Agents) RN - 0 (Quinazolines) RN - 0 (Tyrphostins) RN - 0 (tyrphostin AG 1024) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase) RN - EC 2.7.11.1 (GSK3B protein, human) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - S65743JHBS (Gefitinib) SB - IM MH - Agammaglobulinaemia Tyrosine Kinase MH - Antineoplastic Agents/*pharmacology MH - Apoptosis/drug effects MH - Cell Cycle/drug effects MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Colorectal Neoplasms/*drug therapy/metabolism MH - *Drug Resistance, Neoplasm MH - ErbB Receptors/metabolism MH - Gefitinib MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Humans MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Phosphorylation MH - Protein-Tyrosine Kinases/metabolism MH - Proto-Oncogene Proteins c-met/metabolism MH - Quinazolines/*pharmacology MH - Receptor Cross-Talk MH - *Receptor, IGF Type 1 MH - *Signal Transduction/drug effects MH - Tyrphostins/pharmacology EDAT- 2011/04/12 06:00 MHDA- 2011/10/20 06:00 CRDT- 2011/04/12 06:00 PHST- 2010/11/06 00:00 [received] PHST- 2011/03/23 00:00 [accepted] PHST- 2011/04/12 06:00 [entrez] PHST- 2011/04/12 06:00 [pubmed] PHST- 2011/10/20 06:00 [medline] AID - S1091-255X(23)06000-6 [pii] AID - 10.1007/s11605-011-1504-z [doi] PST - ppublish SO - J Gastrointest Surg. 2011 Jun;15(6):942-57. doi: 10.1007/s11605-011-1504-z. Epub 2011 Apr 9.