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: Sung Keun Jung, Mee-Hyun Lee, Do Young Lim, Jong Eun Kim, Puja Singh, Sung-Young Lee, Chul-Ho Jeong, Tae-Gyu Lim, Hanyong Chen, Young-In Chi, Joydeb Kumar Kundu, Nam Hyouck Lee, Charles C Lee, Yong-Yeon Cho, Ann M Bode, Ki Won Lee, Zigang Dong
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 52 Pg. 35839-48 (Dec 26 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25368326 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• Chalcones
• isoliquiritigenin
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation
• Chalcones (pharmacology)
• ErbB Receptors (antagonists & inhibitors, genetics)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• HEK293 Cells
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mice
• Mice, Nude
• Mutation, Missense
• NIH 3T3 Cells
• Protein Binding
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-akt (metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays