title: Induction of Endoplasmic Reticulum Stress via Reactive Oxygen Species Mediated by Luteolin in Melanoma Cells.
abstract: BACKGROUND
  This study aimed to investigate whether luteolin, a flavonoid, induces apoptosis in human melanoma cells via endoplasmic reticulum (ER) stress.
  
  
  METHODS
  To investigate the effects of luteolin in human melanoma cells, the anti-proliferation, apoptosis, ER stress induction and reactive oxygen species (ROS) generation were evaluated using MTT, Hoechst 33342, ER-tracker Blue White DPX and DCF-DA staining assays, respectively.
  
  
  RESULTS
  Luteolin inhibited cell proliferation and increased apoptotic body formation. Luteolin induced ER stress, as shown by ER staining and mitochondrial Ca(2+) overloading. Luteolin increased expression of the ER stress-related proteins; protein kinase RNA-like ER kinase, phospho eukaryotic translation initiation factor 2α, activating transcription factor (ATF) 6, CCAAT/enhancer-binding protein-homologous protein (CHOP), and cleaved caspase 12. Furthermore, luteolin increased the level of intracellular ROS, leading to ROS-mediated apoptosis and ER stress. However, N-acetyl cysteine, a ROS scavenger, decreased ROS levels, apoptosis, and ER stress induced by luteolin treatment. In addition, knockdown of CHOP and ATF6 by small-interfering RNA inhibited luteolin-induced cell death.
  
  
  CONCLUSIONS
  Luteolin induces apoptosis by ER stress via increasing ROS levels.
authors.affiliation: Department of Bio and Nanochemistry, Kookmin University, Seoul, Republic of Korea.
authors.forename: Joon Ki
authors.initials: JK
authors.lastname: Kim
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Kyoung Ah
authors.initials: KA
authors.lastname: Kang
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Yea Seong
authors.initials: YS
authors.lastname: Ryu
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Mei Jing
authors.initials: MJ
authors.lastname: Piao
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Xia
authors.initials: X
authors.lastname: Han
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Min Chang
authors.initials: MC
authors.lastname: Oh
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Sun Jin
authors.initials: SJ
authors.lastname: Boo
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Seung Uk
authors.initials: SU
authors.lastname: Jeong
authors.affiliation: Department of Bio and Nanochemistry, Kookmin University, Seoul, Republic of Korea.
authors.forename: Yong Joo
authors.initials: YJ
authors.lastname: Jeong
authors.affiliation: KM Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
authors.forename: Sungwook
authors.initials: S
authors.lastname: Chae
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Na
authors.affiliation: School of Medicine, Jeju National University, Jeju, Republic of Korea jinwonh@jejunu.ac.kr sktndud@hanmail.net.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Hyun
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000032:analysis; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology*; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species; D013194:Staining and Labeling; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics; D014162:Transfection; D014410:Tumor Stem Cell Assay
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C497249:DDIT3 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D047311:Luteolin; D002118:Calcium
keywords: Ca2+ overloading; ER stress; Luteolin; Reactive oxygen species; melanoma