title: Decursin enhances TRAIL-induced apoptosis through oxidative stress mediated- endoplasmic reticulum stress signalling in non-small cell lung cancers.
abstract: OBJECTIVE
  The TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent due to its remarkable ability to selectively kill tumour cells. However, because most tumours exhibit resistance to TRAIL-induced apoptosis, the development of combination therapies to overcome resistance to TRAIL is required for effective cancer therapy.
  
  
  METHODS
  Cell viability and possible synergy between the plant pyranocoumarin decursin and TRAIL was measured by MTT assay and calcusyn software. Reactive oxygen species (ROS) and apoptosis were measured using dichlorodihydrofluorescein and annexin/propidium iodide in cell flow cytometry. Changes in protein levels were assessed with Western blotting.
  
  
  RESULTS
  Combining decursin and TRAIL markedly decreased cell viability and increased apoptosis in TRAIL-resistant non-small-cell lung cancer (NSCLC) cell lines. Decursin induced expression of the death receptor 5 (DR5). Inhibition of DR5 attenuated apoptotic cell death in decursin + TRAIL treated NSCLC cell lines. Interestingly, induction of DR5 and CCAAT/enhancer-binding protein homologues protein by decursin was mediated through selective induction of the pancreatic endoplasmic reticulum kinase (PERK)/activating transcription factor 4 (ATF4) branch of the endoplasmic reticulum stress response pathway. Furthermore, enhancement of PERK/ATF4 signalling by decursin was mediated by ROS generation in NSCLC cell lines, but not in normal human lung cells. Decursin also markedly down-regulated expression of survivin and Bcl-xL in TRAIL-resistant NSCLC cells.
  
  
  CONCLUSIONS
  ROS generation by decursin selectively activated the PERK/ATF4 axis of the endoplasmic reticulum stress signalling pathway, leading to enhanced TRAIL sensitivity in TRAIL-resistant NSCLC cell lines, partly via up-regulation of DR5.
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Miyong
authors.initials: M
authors.lastname: Yun
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Eun-Ok
authors.initials: EO
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Deok-Beom
authors.initials: DB
authors.lastname: Jung
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Gunho
authors.initials: G
authors.lastname: Won
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Bonglee
authors.initials: B
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D001578:Benzopyrans; D002087:Butyrates; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D051701:Activating Transcription Factor 4; C101278:decursin; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase