title: Mitogen-activated protein kinase-activated protein kinase 2 mediates resistance to hydrogen peroxide-induced oxidative stress in human hepatobiliary cancer cells.
abstract: The development and progression of liver cancer are characterized by increased levels of reactive oxygen species (ROS). ROS-induced oxidative stress impairs cell proliferation and ultimately leads to cell death. Although liver cancer cells are especially resistant to oxidative stress, mechanisms of such resistance remain understudied. We identified the MAPK-activated protein kinase 2 (MK2)/heat shock protein 27 (Hsp27) signaling pathway mediating defenses against oxidative stress. In addition to MK2 and Hsp27 overexpression in primary liver tumors compared to adjacent nontumorous tissues, the MK2/Hsp27 pathway is activated by hydrogen peroxide-induced oxidative stress in hepatobiliary cancer cells. MK2 inactivation or inhibition of MK2 or Hsp27 expression increases caspase-3 and PARP cleavage and DNA breaks and therefore cell death. Interestingly, MK2/Hsp27 inhibition decreases antioxidant defenses such as heme oxygenase 1 through downregulation of the transcription factor nuclear factor erythroid-derived 2-like 2. Moreover, MK2/Hsp27 inhibition decreases both phosphorylation of epidermal growth factor receptor (EGFR) and expression of its ligand, heparin-binding EGF-like growth factor. A new identified partner of MK2, the scaffold PDZ protein EBP50, could facilitate these effects through MK2/Hsp27 pathway regulation. These findings demonstrate that the MK2/Hsp27 pathway actively participates in resistance to oxidative stress and may contribute to liver cancer progression.
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Thanh Huong
authors.initials: TH
authors.lastname: Nguyen Ho-Bouldoires
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Clapéron
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Mergey
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Service d'Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Desbois-Mouthon
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Sylvana
authors.initials: S
authors.lastname: Tahraoui
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Service d'Hépatologie, AP-HP, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fartoux
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Hamza
authors.initials: H
authors.lastname: Chettouh
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Merabtene
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Service de Chirurgie Hépato-Biliaire et Transplantation Hépatique, AP-HP, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Scatton
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Praz
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Service d'Hépatologie, AP-HP, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.affiliation: INSERM UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France. Electronic address: laura.fouassier@inserm.fr.
authors.forename: Laura
authors.initials: L
authors.lastname: Fouassier
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; 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 / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D055551:HSP27 Heat-Shock Proteins; D006861:Hydrogen Peroxide; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D016877:Oxidants; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000099190:MAP-Kinase-Activated Kinase 2
keywords: Cholangiocarcinoma; EBP50/NHERF-1; EGFR; Free radicals; Hepatocellular carcinoma; Hydrogen peroxide; MAPKAPK2; Reactive oxygen species