title: The chalcone 2'-hydroxy-4',5'-dimethoxychalcone activates death receptor 5 pathway and leads to apoptosis in human nonsmall cell lung cancer cells.
abstract: Natural chalcones have been proved to inhibit cancer cells with therapeutic potential, but the underlying molecular mechanism is still largely unexplored. Here, we identified a novel chalcone, 2'-hydroxy-4',5'-dimethoxychalcone (HDMC) and demonstrated that HDMC induced apoptosis in various nonsmall cell lung cancer cells. Further study showed that HDMC elevated cellular reactive oxygen species (ROS) levels, thus inducing expressions of ATF4 and C/EBP homologous protein (CHOP). Then, death receptor 5 (DR5) was upregulated through ATF4-CHOP axis and eventually resulted in apoptosis. We also found that downregulation of c-FLIPL contributed to HDMC-induced apoptosis. In conclusion, HDMC induces apoptosis in human nonsmall cell lung cancer cells via activation of DR5 signaling pathway, and ROS-mediated ATF4-CHOP axis is involved in the process. Our results further supported the potential for HDMC to be developed as a new antitumor agent for cancer therapy or chemoprevention.
authors.affiliation: Division of Cell Biology, School of Life Sciences, Shandong University, Jinan, People's Republic of China.
authors.forename: Lina
authors.initials: L
authors.lastname: Yang
authors.forename: Ling
authors.initials: L
authors.lastname: Su
authors.forename: Congmei
authors.initials: C
authors.lastname: Cao
authors.forename: Linyan
authors.initials: L
authors.lastname: Xu
authors.forename: Diansheng
authors.initials: D
authors.lastname: Zhong
authors.forename: Lijia
authors.initials: L
authors.lastname: Xu
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Liu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002599:Chalcone; D047188:Chalcones / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C586972:2'-hydroxy-4',5'-dimethoxychalcone; C497109:ATF4 protein, human; D000972:Antineoplastic Agents, Phytogenic; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047188:Chalcones; C497249:DDIT3 protein, human; D004365:Drugs, Chinese Herbal; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D002599:Chalcone
keywords: DR5; ROS; apoptosis; c-FLIP; chalcone