title: Toyocamycin induces apoptosis via the crosstalk between reactive oxygen species and p38/ERK MAPKs signaling pathway in human prostate cancer PC-3 cells.
abstract: BACKGROUND
  Toyocamycin, an antibiotic agent isolated from Streptomyces species, has been shown to have anticancer and chemopreventive effects on various cancer cells. Until now, Toyocamycin-induced apoptosis has not been reported to be involved in the regulation between mitogen-activated protein kinases (MAPKs) and reactive oxygen species (ROS) production.
  
  
  METHODS
  Cell viability assay, western blot, cell-cycle arrest, annexin V/propidium iodide assay, reactive oxygen species (ROS) production, mitochondrial membrane potential and intracellular Ca2+flux were assayed.
  
  
  RESULTS
  We investigated the apoptotic effect of Toyocamycin and the underlying molecular mechanism in prostate cancer PC-3 cells. Toyocamycin treatment resulted in reduced cell viability of PC-3 cells, but not of non-malignant RWPE-1 cells. Toyocamycin enhanced apoptosis, mitochondrial dysfunction, and ROS production in PC-3 cells. In addition, MAPK proteins were activated upon Toyocamycin treatment. The p38 and extracellular signal-regulated kinases (ERK) activities were regulated by ROS-mediated signaling pathway underlying the Toyocamycin-induced apoptosis. Pretreatment with N-acetyl-l-cysteine (NAC) recovered the Toyocamycin-induced mitochondrial dysfunction, ROS, and apoptosis. Additionally, p38 stimulated ROS production and inhibitory effects on ERK activation, while ERK inhibited the ROS production and had no effect on p38 activation.
  
  
  CONCLUSIONS
  ROS-mediated activation of p38/ERK partially contributes to Toyocamycin-induced apoptosis, and p38/ERK MAPKs regulate the ROS production in PC-3 cells.
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yagnsan 50612, Republic of Korea.
authors.forename: Sul-Gi
authors.initials: SG
authors.lastname: Park
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yagnsan 50612, Republic of Korea.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Herbal Formula, Medical Research Center (MRC-GHF), College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.
authors.forename: Kwang-Youn
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yagnsan 50612, Republic of Korea.
authors.forename: Sun-Nyoung
authors.initials: SN
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yagnsan 50612, Republic of Korea.
authors.forename: Hyeun-Deok
authors.initials: HD
authors.lastname: Choi
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yagnsan 50612, Republic of Korea.
authors.forename: Young-Wook
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yagnsan 50612, Republic of Korea.
authors.forename: Hyo-Won
authors.initials: HW
authors.lastname: Nam
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
authors.forename: Young-Kyo
authors.initials: YK
authors.lastname: Seo
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yagnsan 50612, Republic of Korea. Electronic address: ahnsc@pusan.ac.kr.
authors.forename: Soon-Cheol
authors.initials: SC
authors.lastname: Ahn
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014127:Toyocamycin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014127:Toyocamycin
keywords: Apoptosis; Extracellular signal-regulated kinases; Reactive oxygen species; Toyocamycin