title: Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway.
abstract: Fisetin (3,3',4',7-tetrahydroxyflavone), a dietary flavonoid compound, is currently being investigated for its anticancer effect in various cancer models, including lung cancer. Recent studies show that fisetin induces cell growth inhibition and apoptosis in the human non-small cell lung cancer line NCI-H460. In this study, we investigated whether fisetin can induce endoplasmic reticulum (ER) stress-mediated apoptosis in NCI-H460 cells. Fisetin induced mitochondrial reactive oxygen species (ROS) and characteristic signs of ER stress: ER staining; mitochondrial Ca(2+) overload; expression of ER stress-related proteins; glucose-regulated protein (GRP)-78, phosphorylation of protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylation of eukaryotic initiation factor-2 α subunit; cleavage of activating transcription factor-6; phosphorylation of inositol-requiring kinase-1 and splicing of X-box transcription factor-1; induction of C/EBP homologous protein and cleaved caspase-12. siRNA-mediated knockdown of CHOP and ATF-6 attenuated fisetin-induced apoptotic cell death. In addition, fisetin induced phosphorylation of ERK, JNK, and p38 MAPK. Moreover, silencing of the MAPK signaling pathway prevented apoptotic cell death. In summary, our results indicate that, in NCI-H460 cells, fisetin induces apoptosis and ER stress that is mediated by induction of the MAPK signaling pathway.
authors.affiliation: Department of Biochemistry, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
authors.forename: Kyoung Ah
authors.initials: KA
authors.lastname: Kang
authors.affiliation: Department of Biochemistry, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
authors.forename: Mei Jing
authors.initials: MJ
authors.lastname: Piao
authors.affiliation: Department of Biochemistry, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
authors.forename: Susara Ruwan Kumara
authors.initials: SR
authors.lastname: Madduma Hewage
authors.affiliation: Department of Biochemistry, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
authors.forename: Yea Seong
authors.initials: YS
authors.lastname: Ryu
authors.affiliation: Department of Biochemistry, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
authors.forename: Min Chang
authors.initials: MC
authors.lastname: Oh
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.affiliation: Aging Research Center, Korea Institute of Oriental Medicine, Daejeon, 34054, Republic of Korea.
authors.forename: Sungwook
authors.initials: S
authors.lastname: Chae
authors.affiliation: Department of Biochemistry, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea. jinwonh@jejunu.ac.kr.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Hyun
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D005419:Flavonoids; D044948:Flavonols; D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases; C017875:fisetin
keywords: Apoptosis; ER stress; Fisetin; Human non-small cell lung cancer; MAPK signaling pathway; Reactive oxygen species