title: Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy-Terminal Domain.
abstract: Macrophage elastase (matrix metalloproteinase [MMP]-12) is a potent protease that contributes to the lung destruction that accompanies cigarette smoking; it simultaneously inhibits lung tumor angiogenesis and metastasis by catalyzing the formation of antiangiogenic peptides. Recent studies have revealed novel nonproteolytic functions of MMP12, including antimicrobial activity through a peptide within its C-terminal domain (CTD).
  
  
  
  To determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer.
  
  
  
  We used recombinant MMP12 peptide fragments, including its catalytic domain, CTD, and a 20 amino acid peptide within the CTD (SR20), in an in vitro system to delineate their effects on non-small cell lung cancer cell proliferation and apoptosis. We translated our findings to two murine models of lung cancer, including orthotopic human xenograft and KrasLSL/G12Dmouse models of lung cancer.
  
  
  
  We show that SR20 triggers tumor apoptosis by up-regulation of gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4, sensitizing cells to an autocrine loop of TRAIL-mediated cell death. We then demonstrate the therapeutic efficacy of SR20 against two murine models of lung cancer.
  
  
  
  The MMP12 CTD initiates TRAIL-mediated tumor cell death through its conserved SR20 peptide.
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Nadine
authors.initials: N
authors.lastname: Dandachi
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Kelly
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: John P
authors.initials: JP
authors.lastname: Wood
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Burton
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Josiah E
authors.initials: JE
authors.lastname: Radder
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Leme
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Alyssa D
authors.initials: AD
authors.lastname: Gregory
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D051379:Mice; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D053508:Matrix Metalloproteinase 12
keywords: apoptosis; lung cancer; matrix metalloproteinase-12; proteases; tumor necrosis factor–related apoptosis-inducing ligand