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Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death Through Its Carboxy-Terminal Domain

Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death Through Its Carboxy-Terminal Domain

Nadine Dandachi, Neil J Kelly, John P Wood, Christine L Burton, Josiah E Radder, Adriana S Leme, Alyssa D Gregory, Steven D Shapiro

Am J Respir Crit Care Med. 2017 Aug 1;196(3):353-363.

PMID: 28345958

Abstract:

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 KrasLSL/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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4241276	Matrix Metalloproteinase-12, Catalytic Domain human			Price

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