Isoliquiritigenin induces apoptosis and inhibits xenograft tumor growth of human lung cancer cells by targeting both wild type and L858R/T790M mutant EGFR. J Biol Chem 2014 Dec 26;289(52):35839-48
Date
11/05/2014Pubmed ID
25368326Pubmed Central ID
PMC4276852DOI
10.1074/jbc.M114.585513Scopus ID
2-s2.0-84937120687 (requires institutional sign-in at Scopus site) 97 CitationsAbstract
Non-small-cell lung cancer (NSCLC) is associated with diverse genetic alterations including mutation of epidermal growth factor receptor (EGFR). Isoliquiritigenin (ILQ), a chalcone derivative, possesses anticancer activities. In the present study, we investigated the effects of ILQ on the growth of tyrosine kinase inhibitor (TKI)-sensitive and -resistant NSCLC cells and elucidated its underlying mechanisms. Treatment with ILQ inhibited growth and induced apoptosis in both TKI-sensitive and -resistant NSCLC cells. ILQ-induced apoptosis was associated with the cleavage of caspase-3 and poly-(ADP-ribose)-polymerase, increased expression of Bim, and reduced expression of Bcl-2. In vitro kinase assay results revealed that ILQ inhibited the catalytic activity of both wild type and double mutant (L858R/T790M) EGFR. Treatment with ILQ inhibited the anchorage-independent growth of NIH3T3 cells stably transfected with either wild type or double-mutant EGFR with or without EGF stimulation. ILQ also reduced the phosphorylation of Akt and ERK1/2 in both TKI-sensitive and -resistant NSCLC cells, and attenuated the kinase activity of Akt1 and ERK2 in vitro. ILQ directly interacted with both wild type and double-mutant EGFR in an ATP-competitive manner. A docking model study showed that ILQ formed two hydrogen bonds (Glu-762 and Met-793) with wild type EGFR and three hydrogen bonds (Lys-745, Met-793, and Asp-855) with mutant EGFR. ILQ attenuated the xenograft tumor growth of H1975 cells, which was associated with decreased expression of Ki-67 and diminished phosphorylation of Akt and ERK1/2. Taken together, ILQ suppresses NSCLC cell growth by directly targeting wild type or mutant EGFR.
Author List
Jung SK, Lee MH, Lim DY, Kim JE, Singh P, Lee SY, Jeong CH, Lim TG, Chen H, Chi YI, Kundu JK, Lee NH, Lee CC, Cho YY, Bode AM, Lee KW, Dong ZAuthor
Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents, Phytogenic
Apoptosis
Cell Line, Tumor
Cell Proliferation
Chalcones
ErbB Receptors
Extracellular Signal-Regulated MAP Kinases
HEK293 Cells
Humans
Lung Neoplasms
Mice
Mice, Nude
Mutation, Missense
NIH 3T3 Cells
Protein Binding
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt
Tumor Burden
Xenograft Model Antitumor Assays