title: CREB-induced inflammation is important for malignant mesothelioma growth.
abstract: Malignant mesothelioma (MM) is an aggressive tumor with no treatment regimen. Previously we have demonstrated that cyclic AMP response element binding protein (CREB) is constitutively activated in MM tumor cells and tissues and plays an important role in MM pathogenesis. To understand the role of CREB in MM tumor growth, we generated CREB-inhibited MM cell lines and performed in vitro and in vivo experiments. In vitro experiments demonstrated that CREB inhibition results in significant attenuation of proliferation and drug resistance of MM cells. CREB-silenced MM cells were then injected into severe combined immunodeficiency mice, and tumor growth in s.c. and i.p. models of MM was followed. We observed significant inhibition in MM tumor growth in both s.c. and i.p. models and the presence of a chemotherapeutic drug, doxorubicin, further inhibited MM tumor growth in the i.p. model. Peritoneal lavage fluids from CREB-inhibited tumor-bearing mice showed a significantly reduced total cell number, differential cell counts, and pro-inflammatory cytokines and chemokines (IL-6, IL-8, regulated on activation normal T cell expressed and secreted, monocyte chemotactic protein-1, and vascular endothelial growth factor). In vitro studies showed that asbestos-induced inflammasome/inflammation activation in mesothelial cells was CREB dependent, further supporting the role of CREB in inflammation-induced MM pathogenesis. In conclusion, our data demonstrate the involvement of CREB in the regulation of MM pathogenesis by regulation of inflammation.
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Westbom
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Anurag
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Maximilian B
authors.initials: MB
authors.lastname: MacPherson
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Yasewicz
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Miller
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Stacie L
authors.initials: SL
authors.lastname: Beuschel
authors.affiliation: Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.affiliation: Langone Medical Center, NYU School of Medicine, New York, New York.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: Department of Medical Biostatistics, College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Vacek
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont. Electronic address: arti.shukla@uvm.edu.
authors.forename: Arti
authors.initials: A
authors.lastname: Shukla
mesh_terms: D000818:Animals; D001194:Asbestos / Q000009:adverse effects; D050882:CREB-Binding Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D018925:Chemokines; D015850:Interleukin-6; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D001194:Asbestos; D004317:Doxorubicin; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse
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