title: Isoliquiritigenin induces apoptosis and inhibits xenograft tumor growth of human lung cancer cells by targeting both wild type and L858R/T790M mutant EGFR.
abstract: 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.
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912, Division of Metabolism and Functionality Research, Korea Food Research Institute, Seongnam, Gyeonggi-do, 463-746 Republic of Korea.
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912, College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 420-743 South Korea.
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Lim
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912, Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, 443-270 South Korea.
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912.
authors.forename: Puja
authors.initials: P
authors.lastname: Singh
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912.
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912, College of Pharmacy, Keimyung University, Daegu, 704-701 South Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Jeong
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912, WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, 151-921, Republic of Korea.
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Lim
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912.
authors.forename: Young-In
authors.initials: YI
authors.lastname: Chi
authors.affiliation: College of Pharmacy, Keimyung University, Daegu, 704-701 South Korea.
authors.forename: Joydeb Kumar
authors.initials: JK
authors.lastname: Kundu
authors.affiliation: Division of Metabolism and Functionality Research, Korea Food Research Institute, Seongnam, Gyeonggi-do, 463-746 Republic of Korea.
authors.forename: Nam Hyouck
authors.initials: NH
authors.lastname: Lee
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912, Department of Food Science, Cornell University, Ithaca, New York 14850, and.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Lee
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 420-743 South Korea.
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, 443-270 South Korea, WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, 151-921, Republic of Korea, Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, 232-916, Republic of Korea kiwon@snu.ac.kr.
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.affiliation: From The Hormel Institute, University of Minnesota, Minnesota 55912, zgdong@hi.umn.edu.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047188:Chalcones / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047188:Chalcones; C040920:isoliquiritigenin; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Apoptosis; Cell Growth; Epidermal Growth Factor Receptor (EGFR); Lung Cancer; Tyrosine-Protein Kinase (Tyrosine Kinase)