title: Cryptotanshinone deregulates unfolded protein response and eukaryotic initiation factor signaling in acute lymphoblastic leukemia cells.
abstract: BACKGROUND
  Unfolded protein responses (UPR) determine cell fate and are recognized as anticancer targets. In a previous research, we reported that cryptotanshinone (CPT) exerted cytotoxic effects toward acute lymphoblastic leukemia cells through mitochondria-mediated apoptosis.
  
  
  OBJECTIVE
  In the present study, we further investigated the role of UPR in CPT-induced cytotoxicity on acute lymphoblastic leukemia cells by applying tools of pharmacogenomics and bioinformatics.
  
  
  METHODS
  Gene expression profiling was performed by mRNA microarray hybridization. Potential transcription factor binding motifs were identified in the promoter regions of the deregulated genes by Cistrome software. Molecular docking on eIF-4A and PI3K was performed to investigate the inhibitory activity of CPT on translation initiation.
  
  
  RESULTS
  CPT regulated genes related to UPR and eIF2 signaling pathways. The DNA-Damage-Inducible Transcript 3 (DDIT3) gene, which is activated as consequence of UPR malfunction during apoptosis, was induced and validated by in vitro experiments. Transcription factor binding motif analysis of the microarrary-retrieved deregulated genes in the promoter region emphasized the relevance of transcription factors, such as ATF2, ATF4 and XBP1, regulating UPR and cell apoptosis. Molecular docking suggested inhibitory effects of CPT by binding to eIF-4A and PI3K providing evidence for a role of CPT's in the disruption of protein synthesis.
  
  
  CONCLUSIONS
  CPT triggered UPR and inhibited protein synthesis via eIF-mediated translation initiation, potentially supporting CPT-induced cytotoxic effects toward acute leukemia cells.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Ching-Fen
authors.initials: CF
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Ean-Jeong
authors.initials: EJ
authors.lastname: Seo
authors.affiliation: Working Group Cancer Genome Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Klauck
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019295:Computational Biology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D010597:Pharmacogenetics; D010616:Phenanthrenes / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; D039642:Eukaryotic Initiation Factors; D010616:Phenanthrenes; D012333:RNA, Messenger; D014157:Transcription Factors; D051742:Transcription Factor CHOP; C037886:cryptotanshinone; D019869:Phosphatidylinositol 3-Kinases; D039601:Eukaryotic Initiation Factor-4A
keywords: Cryptotanshinone; DDIT3; Eukaryotic initiation factor (eIF); Pharmacogenetics; Salvia miltiorrhiza Bunge (Lamiaceae); Unfolded protein response (UPR)