title: Des-gamma-carboxy prothrombin (DCP) antagonizes the effects of gefitinib on human hepatocellular carcinoma cells.
abstract: OBJECTIVE
  Des-gamma-carboxy prothrombin (DCP), an aberrant prothrombin produced by hepatocellular carcinoma (HCC) cells, is known as a marker for HCC. Recent studies indicated that high levels of DCP are associated with the malignant potential of HCC. In this study, we aimed to investigate the association of DCP with gefitinib treatment failure in HCC and whether DCP counteracts gefitinib-induced growth inhibition and apoptosis of HCC.
  
  
  METHODS
  The experiments were performed in HCC cell lines HepG2 and PLC/PRF/5. The effects of gefitinib on HCC in the presence or absence of DCP were evaluated by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Apoptotic cells were identified by Annexin V-FITC/PI staining. Western blotting was performed to analyze the expressions of molecules related to the apoptotic caspase-dependent pathway and epidermal growth factor receptor (EGFR) pathway.
  
  
  RESULTS
  Gefitinib inhibited HCC cell proliferation and induced apoptosis in HCC cells. The effects of gefitinib on HCC cells were antagonized by DCP. In the presence of DCP, HCC cells were resistant to the gefitinib-induced inhibition of proliferation and stimulation of apoptosis. DCP prevented the activation of the apoptotic caspase-dependent pathway induced by gefitinib. These antagonistic effects of DCP also arose from its ability to up-regulate EGFR, c-Met and hepatocyte growth factor (HGF) in HCC cells.
  
  
  CONCLUSIONS
  DCP antagonized gefitinib-induced HCC cell growth inhibition by counteracting apoptosis and up-regulating the EGFR pathway. High levels of DCP might thus lead to low response rates or possibly no response to gefitinib in patients with HCC.
authors.affiliation: Evaluation Center for Food and Drug, Capital Medical University, Beijing, China.
authors.forename: Shu-Xiang
authors.initials: SX
authors.lastname: Cui
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Zhang
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Chu
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Song
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Qu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000494:pharmacology*; D011516:Prothrombin / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D011498:Protein Precursors; D011799:Quinazolines; C008208:acarboxyprothrombin; D017228:Hepatocyte Growth Factor; D011516:Prothrombin; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020169:Caspases; D000077156:Gefitinib