Content area

Full text

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 xenograftand 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.

Keywords: matrix metalloproteinase-12; tumor necrosis factor-related apoptosis-inducing ligand; proteases; lung cancer; apoptosis

Lung cancer is the leading cause of cancer mortality in the United States, and despite recent progress in the management of many cancers, death rates among patients with lung cancer remain alarmingly high (1). Lung cancer is strongly correlated to a history of cigarette smoking (2), which is accompanied by damage and remodeling cycles that underlie the pathogeneses of other smoking-related diseases (3). Matrix metalloproteinases (MMPs) are among the key endogenous mediators of these alterations in lung structure and function (4-6), and MMPs also play critical roles in tumor biology. Although the overall effect of MMPs is to promote tumor progression (7), some MMPs, particularly MMP12, seem to work for the host in inhibiting tumor progression (8, 9).

The MMPs constitute a family of 24 members with many common functional and structural characteristics, including an amino-terminal proenzyme domain and a zinc-containing catalytic domain. Most MMPs also contain a carboxy-terminal hemopexin-like domain, whereas some possess additional features, such as a transmembrane domain (10). In...

Show less