title: miR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death.
abstract: BACKGROUND
  Pancreatic cancer is one of the most lethal human malignancies, with an all-stage 5-year survival of <5%, mainly due to lack of effective available therapies. Cancer cell survival is dependent upon up-regulation of the pro-survival response, mediated by anti-apoptotic proteins such as Mcl-1.
  
  
  RESULTS
  Here we show that over-expression of Mcl-1 in pancreatic patient tumor samples is linked to advancement of the disease. We have previously shown that triptolide, a diterpene triepoxide, is effective both in vitro and in vivo, in killing pancreatic cancer cells. Decrease of Mcl-1 levels, either by siRNA or by treatment with triptolide results in cell death. Using pancreatic cancer cell lines, we have shown that miR-204, a putative regulator of Mcl-1, is repressed in cancer cell lines compared to normal cells. Over-expression of miR-204, either by a miR-204 mimic, or by triptolide treatment results in a decrease in Mcl-1 levels, and a subsequent decrease in cell viability. Using luciferase reporter assays, we confirmed the ability of miR-204 to down-regulate Mcl-1 by directly binding to the Mcl-1 3' UTR. Using human xenograft samples treated with Minnelide, a water soluble variant of triptolide, we have shown that miR-204 is up-regulated and Mcl-1 is down-regulated in treated vs. control tumors.
  
  
  CONCLUSIONS
  Triptolide mediated miR-204 increase causes pancreatic cancer cell death via loss of Mcl-1.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. asaluja@umn.edu.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Chen
authors.forename: Veena
authors.initials: V
authors.lastname: Sangwan
authors.forename: Sulagna
authors.initials: S
authors.lastname: Banerjee
authors.forename: Tiffany
authors.initials: T
authors.lastname: Mackenzie
authors.forename: Vikas
authors.initials: V
authors.lastname: Dudeja
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Li
authors.forename: Huaizhi
authors.initials: H
authors.lastname: Wang
authors.forename: Selwyn M
authors.initials: SM
authors.lastname: Vickers
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Saluja
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D016923:Cell Death; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000502:physiology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D010755:Organophosphates / Q000494:pharmacology; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology; D034622:RNA Interference; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; C579095:MCL1 protein, human; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010755:Organophosphates; D010616:Phenanthrenes; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt
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