title: Phosphorylated insulin-like growth factor 1 receptor is implicated in resistance to the cytostatic effect of gefitinib in colorectal cancer cells.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Ran
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Zhao
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ding
authors.forename: Yuying
authors.initials: Y
authors.lastname: Chen
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Peng
authors.forename: Houjie
authors.initials: H
authors.lastname: Liang
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D000077156:Gefitinib