Matrix metalloproteinase-26 is associated with estrogen-dependent malignancies and targets α1-antitrypsin serpin

Wei Li, Alexei Y. Savinov, Dmitri Rozanov, Vladislav S. Golubkov, Hirad Hedayat, Tatiana I. Postnova, Natalia V. Golubkova, Yu Linli, Stanislaw Krajewski, Alex Y. Strongin

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Proteases exert control over cell behavior and affect many biological processes by making proteolytic modification of regulatory proteins. The purpose of this paper is to describe novel, important functions of matrix metalloproteinase (MMP)-26. α1-Antitrypsin (AAT) is a serpin, the primary function of which is to regulate the activity of neutrophil/leukocyte elastase. Insufficient antiprotease activity because of AAT deficiency in the lungs is a contributing factor to early-onset emphysema. We recently discovered that AAT is efficiently cleaved by a novel metalloproteinase, MMP-26, which exhibits an unconventional PH81CGVPD Cys switch motif and is autocatalytically activated in cells and tissues. An elevated expression of MMP-26 in macrophages and polymorphonuclear leukocytes supports the functional role of MMP-26 in the AAT cleavage and inflammation. We have demonstrated a direct functional link of MMP-26 expression with an estrogen dependency and confirmed the presence of the estrogen-response element in the MMP-26 promoter. Immunostaining of tumor cell lines and biopsy specimen microarrays confirmed the existence of the inverse correlations of MMP-26 and AAT in cells/tissues. An expression of MMP-26 in the estrogen-dependent neoplasms is likely to contribute to the inactivation of AAT, to the follow-up liberation of the Ser protease activity, and because of these biochemical events, to promote matrix destruction and malignant progression. In summary, we hypothesize that MMP-26, by cleaving and inactivating the AAT serpin, operates as a unique functional link that regulates a coordinated interplay between Ser and metalloproteinases in estrogen-dependent neoplasms.

Original languageEnglish (US)
Pages (from-to)8657-8665
Number of pages9
JournalCancer Research
Volume64
Issue number23
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

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Serpins
Matrix Metalloproteinases
Estrogens
Neoplasms
Leukocyte Elastase
Metalloproteases
Peptide Hydrolases
Biological Phenomena
Emphysema
Response Elements
Protease Inhibitors
Tumor Cell Line
Neutrophils
Macrophages
Inflammation
Biopsy
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Matrix metalloproteinase-26 is associated with estrogen-dependent malignancies and targets α1-antitrypsin serpin. / Li, Wei; Savinov, Alexei Y.; Rozanov, Dmitri; Golubkov, Vladislav S.; Hedayat, Hirad; Postnova, Tatiana I.; Golubkova, Natalia V.; Linli, Yu; Krajewski, Stanislaw; Strongin, Alex Y.

In: Cancer Research, Vol. 64, No. 23, 01.12.2004, p. 8657-8665.

Research output: Contribution to journalArticle

Li, W, Savinov, AY, Rozanov, D, Golubkov, VS, Hedayat, H, Postnova, TI, Golubkova, NV, Linli, Y, Krajewski, S & Strongin, AY 2004, 'Matrix metalloproteinase-26 is associated with estrogen-dependent malignancies and targets α1-antitrypsin serpin', Cancer Research, vol. 64, no. 23, pp. 8657-8665. https://doi.org/10.1158/0008-5472.CAN-04-3019
Li, Wei ; Savinov, Alexei Y. ; Rozanov, Dmitri ; Golubkov, Vladislav S. ; Hedayat, Hirad ; Postnova, Tatiana I. ; Golubkova, Natalia V. ; Linli, Yu ; Krajewski, Stanislaw ; Strongin, Alex Y. / Matrix metalloproteinase-26 is associated with estrogen-dependent malignancies and targets α1-antitrypsin serpin. In: Cancer Research. 2004 ; Vol. 64, No. 23. pp. 8657-8665.
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AU - Li, Wei

AU - Savinov, Alexei Y.

AU - Rozanov, Dmitri

AU - Golubkov, Vladislav S.

AU - Hedayat, Hirad

AU - Postnova, Tatiana I.

AU - Golubkova, Natalia V.

AU - Linli, Yu

AU - Krajewski, Stanislaw

AU - Strongin, Alex Y.

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