• Nadine Dandachi, Neil J Kelly, John P Wood, Christine L Burton, Josiah E Radder, Adriana S Leme, Alyssa D Gregory, and Steven D Shapiro.
• Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
• Am. J. Respir. Crit. Care Med. 2017 Aug 1; 196 (3): 353-363.

RationaleMacrophage 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).ObjectivesTo determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer.MethodsWe 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/G12D mouse models of lung cancer.Measurements And Main ResultsWe 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.ConclusionsThe MMP12 CTD initiates TRAIL-mediated tumor cell death through its conserved SR20 peptide.

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