Matrix metalloproteinase-activated anthrax lethal toxin inhibits endothelial invasion and neovasculature formation during in vitro morphogenesis

Randall W. Alfano, Stephen H. Leppla, Shihui Liu, Thomas H. Bugge, Cynthia J. Meininger, Terry C. Lairmore, Arlynn F. Mulne, Samuel H. Davis, Nicholas S. Duesbery, Arthur E. Frankel

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Solid tumor growth is dependent on angiogenesis, the formation of neovasculature from existing vessels. Endothelial activation of the extracellular signal-regulated kinase 1/2, c-jun NH 2-terminal kinase, and p38 mitogen-activated protein kinase pathways is central to this process, and thus presents an attractive target for the development of angiogenesis inhibitors. Anthrax lethal toxin (LeTx) has potent catalytic mitogen-activated protein kinase inhibition activity. Preclinical studies showed that LeTx induced potent tumor growth inhibition via the inhibition of xenograft vascularization. However, LeTx receptors and the essential furin-like activating proteases are expressed in many normal tissues, potentially limiting the specificity of LeTx as an antitumor agent. To circumvent nonspecific LeTx activation and simultaneously enhance tumor vascular targeting, a substrate preferably cleaved by the gelatinases class of matrix metalloproteinases (MMP) was substituted for the furin LeTx activation site. In vivo efficacy studies showed that this MMP-activated LeTx inhibited tumor xenografts growth via the reduced migration of endothelial cells into the tumor parenchyma. Here we have expanded on these initial findings by showing that this MMP-activated LeTx reduces endothelial proangiogenic MMP expression, thus causing a diminished proteolytic capacity for extracellular matrix remodeling and endothelial differentiation into capillary networks. Additionally, our data suggest that inhibition of the c-jun NH 2-terminal kinase and p38, but not extracellular signal-regulated kinase-1/2, pathways is significant in the antiangiogenic activity of the MMP-activated LeTx. Collectively, these results support the clinical development of the MMP-activated LeTx for the treatment of solid tumors.

Original languageEnglish (US)
Pages (from-to)452-461
Number of pages10
JournalMolecular Cancer Research
Volume7
Issue number4
DOIs
StatePublished - Apr 1 2009

Fingerprint

Matrix Metalloproteinases
Morphogenesis
Furin
Neoplasms
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Heterografts
Phosphotransferases
Growth
Gelatinases
Angiogenesis Inhibitors
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Antineoplastic Agents
Extracellular Matrix
Blood Vessels
anthrax toxin
In Vitro Techniques
Peptide Hydrolases
Endothelial Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Matrix metalloproteinase-activated anthrax lethal toxin inhibits endothelial invasion and neovasculature formation during in vitro morphogenesis. / Alfano, Randall W.; Leppla, Stephen H.; Liu, Shihui; Bugge, Thomas H.; Meininger, Cynthia J.; Lairmore, Terry C.; Mulne, Arlynn F.; Davis, Samuel H.; Duesbery, Nicholas S.; Frankel, Arthur E.

In: Molecular Cancer Research, Vol. 7, No. 4, 01.04.2009, p. 452-461.

Research output: Contribution to journalArticle

Alfano, Randall W. ; Leppla, Stephen H. ; Liu, Shihui ; Bugge, Thomas H. ; Meininger, Cynthia J. ; Lairmore, Terry C. ; Mulne, Arlynn F. ; Davis, Samuel H. ; Duesbery, Nicholas S. ; Frankel, Arthur E. / Matrix metalloproteinase-activated anthrax lethal toxin inhibits endothelial invasion and neovasculature formation during in vitro morphogenesis. In: Molecular Cancer Research. 2009 ; Vol. 7, No. 4. pp. 452-461.
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AU - Meininger, Cynthia J.

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