期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 196, 期 3, 页码 353-363出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201606-1150OC
关键词
matrix metalloproteinase-12; tumor necrosis factor-related apoptosis-inducing ligand; proteases; lung cancer; apoptosis
资金
- NHLBI [5P01 HL103455, 5T32 HL094295]
- National Institute of General Medical Sciences [5T32 GM008208]
- National Cancer Institute of the National Institutes of Health [5P50 CA090440]
- Flight Attendant Medical Research Institute
Rationale: 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). Objectives: To determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer. Methods: 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 Kras(LSL/G12D) mouse models of lung cancer. Measurements and Main Results: 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. Conclusions: The MMP12 CTD initiates TRAIL-mediated tumor cell death through its conserved SR20 peptide.
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