title: Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas.
abstract: OBJECTIVE
  Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal-regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment.
  
  
  METHODS
  ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models.
  
  
  RESULTS
  We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth.
  
  
  CONCLUSIONS
  ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma.
authors: Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA. Arti.Shukla@med.uvm.edu
authors: Arti
authors: A
authors: Shukla
authors: Jill M
authors: JM
authors: Miller
authors: Christopher
authors: C
authors: Cason
authors: Mutlay
authors: M
authors: Sayan
authors: Maximilian B
authors: MB
authors: MacPherson
authors: Stacie L
authors: SL
authors: Beuschel
authors: Jedd
authors: J
authors: Hillegass
authors: Pamela M
authors: PM
authors: Vacek
authors: Harvey I
authors: HI
authors: Pass
authors: Brooke T
authors: BT
authors: Mossman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017638:Asbestos, Crocidolite / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D017638:Asbestos, Crocidolite; D004317:Doxorubicin; D048054:Mitogen-Activated Protein Kinase 7; D002945:Cisplatin