title: Ubiquitin ligase Cbl-b is involved in icotinib (BPI-2009H)-induced apoptosis and G1 phase arrest of EGFR mutation-positive non-small-cell lung cancer.
abstract: Epidermal growth factor receptor (EGFR) is one of the most promising targets for non-small-cell lung cancer (NSCLC). Icotinib, a highly selective EGFR tyrosine kinase inhibitor (EGFR-TKI), has shown promising clinical efficacy and safety in patients with NSCLC. The exact molecular mechanism of icotinib remains unclear. In this study, we first investigated the antiproliferative effect of icotinib on NSCLC cells. Icotinib significantly inhibited proliferation of the EGFR-mutated lung cancer HCC827 cells. The IC50 values at 48 and 72 h were 0.67 and 0.07 μ M, respectively. Flow cytometric analysis showed that icotinib caused the G1 phase arrest and increased the rate of apoptosis in HCC827 cells. The levels of cyclin D1 and cyclin A2 were decreased. The apoptotic process was associated with activation of caspase-3, -8, and poly(ADP-ribose) polymerase (PARP). Further study revealed that icotinib inhibited phosphorylation of EGFR, Akt, and extracellular signal-regulated kinase. In addition, icotinib upregulated ubiquitin ligase Cbl-b expression. These observations suggest that icotinib-induced upregulation of Cbl-b is responsible, at least in part, for the antitumor effect of icotinib via the inhibition of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase pathways in EGFR-mutated NSCLC cells.
authors.affiliation: Department of Respiratory Medicine, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang 110001, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Mu
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
authors.forename: Kezuo
authors.initials: K
authors.lastname: Hou
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.forename: Xuejun
authors.initials: X
authors.lastname: Hu
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D043844:Crown Ethers / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000235:genetics*; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D043844:Crown Ethers; D011799:Quinazolines; C531470:icotinib; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt