title: Heme oxygenase is not involved in the anti-proliferative effects of statins on pancreatic cancer cells.
abstract: Pancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy. Statins were previously shown to inhibit the proliferation of cancer cells via various signaling pathways. In healthy tissues, statins activate the heme oxygenase pathway, nevertheless the role of heme oxygenase in pancreatic cancer is still controversial. The aim of this study was to evaluate, whether anti-proliferative effects of statins in pancreatic cancer cells are mediated via the heme oxygenase pathway.
  
  
  
  In vitro effects of various statins and hemin, a heme oxygenase inducer, on cell proliferation were evaluated in PA-TU-8902, MiaPaCa-2 and BxPC-3 human pancreatic cancer cell lines. The effect of statins on heme oxygenase activity was assessed and heme oxygenase-silenced cells were used for pancreatic cancer cell proliferation studies. Cell death rate and reactive oxygen species production were measured in PA-TU-8902 cells, followed by evaluation of the effect of cerivastatin on GFP-K-Ras trafficking and expression of markers of invasiveness, osteopontin (SPP1) and SOX2.
  
  
  
  While simvastatin and cerivastatin displayed major anti-proliferative properties in all cell lines tested, pravastatin did not affect the cell growth at all. Strong anti-proliferative effect was observed also for hemin. Co-treatment of cerivastatin and hemin increased anti-proliferative potential of these agents, via increased production of reactive oxygen species and cell death compared to individual treatment. Heme oxygenase silencing did not prevent pancreatic cancer cells from the tumor-suppressive effect of cerivastatin or hemin. Cerivastatin, but not pravastatin, protected Ras protein from trafficking to the cell membrane and significantly reduced expressions of SPP1 (p < 0.05) and SOX2 (p < 0.01).
  
  
  
  Anti-proliferative effects of statins and hemin on human pancreatic cancer cell lines do not seem to be related to the heme oxygenase pathway. While hemin triggers reactive oxygen species-induced cell death, cerivastatin targets Ras protein trafficking and affects markers of invasiveness.
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Katerinska 32, Prague 2, 120 00, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Vanova
authors.affiliation: Institute of Biotechnology, Czech Academy of Sciences, Videnska 1083, Prague 4, 142 20, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Boukalova
authors.affiliation: Department of Biochemistry and Microbiology, University of Chemistry and Technology, Technicka 1905/5, Prague 6, 160 00, Czech Republic.
authors.forename: H
authors.initials: H
authors.lastname: Gbelcova
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Katerinska 32, Prague 2, 120 00, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Muchova
authors.affiliation: Institute of Biotechnology, Czech Academy of Sciences, Videnska 1083, Prague 4, 142 20, Czech Republic.|School of Medical Science, Griffith University, Parklands Avenue, 4222, Southport, QLD, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Neuzil
authors.affiliation: Department of Surgery, University Hospital Kralovske Vinohrady and Charles University in Prague, Srobarova 50, Prague 10, 100 34, Czech Republic.
authors.forename: R
authors.initials: R
authors.lastname: Gurlich
authors.affiliation: Department of Biochemistry and Microbiology, University of Chemistry and Technology, Technicka 1905/5, Prague 6, 160 00, Czech Republic.
authors.forename: T
authors.initials: T
authors.lastname: Ruml
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Katerinska 32, Prague 2, 120 00, Czech Republic. vitek@cesnet.cz.|4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University in Prague, Katerinska 32, Prague 2, 120 00, Czech Republic. vitek@cesnet.cz.
authors.forename: L
authors.initials: L
authors.lastname: Vitek
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D018631:ras Proteins
keywords: Heme; Heme oxygenase; Pancreatic cancer; Statins