Membrane type-1 matrix metalloproteinase (MT1-MMP) protects malignant cells from tumoricidal activity of re-engineered anthrax lethal toxin

Dmitri V. Rozanov, Vladislav S. Golubkov, Alex Y. Strongin

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Protective antigen (PA) and lethal factor (LF) are the two components of anthrax lethal toxin. PA is responsible for interacting with cell receptors and for the subsequent translocation of LF inside the cell compartment. A re-engineered toxin comprised of PA and a fusion chimera LF/Pseudomonas exotoxin (FP59) is a promising choice for tumor cell surface targeting. We demonstrated, however, that in vitro in cell-free system and in cultured human colon carcinoma LoVo, fibrosarcoma HT1080 and glioma U251 cells membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves both the PA83 precursor and the PA63 mature protein. Exhaustive MT1-MMP cleavage of PA83 in vitro generates several major degradation fragments with an N-terminus at Glu40, Leu48, and Gln512. In cultured cells, MT1-MMP-dependent cleavage releases the cell-bound PA83 and PA63 species from the cell surface. As a result, MT1-MMP expressing cells have less PA63 to internalize. In agreement, our observations demonstrate that MT1-MMP proteolysis of PA makes the MT1-MMP-expressing aggressive invasive cells resistant to the cytotoxic effect of a bipartite PA/FP59 toxin. We infer from our studies that synthetic inhibitors of MMPs are likely to increase the therapeutic anti-cancer effect of anthrax toxin. In addition, our study supports a unique role of furin in the activation of PA, thereby suggesting that furin inhibitors are the likely specific drugs for short-term therapy of anthrax infection.

Original languageEnglish (US)
Pages (from-to)142-154
Number of pages13
JournalInternational Journal of Biochemistry and Cell Biology
Volume37
Issue number1
DOIs
StatePublished - Jan 1 2005

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Keywords

  • DMEM
  • Dulbecco's MEM
  • EF
  • FP59
  • LF
  • edema factor
  • fusion protein 59 (a chimera in which LF residues 1-254 have been fused with the ADP-ribosylation domain III of Pseudomonas exotoxin A)
  • lethal factor
  • lysis buffer

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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