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Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways

  1. Author:
    Duesbery, N. S.
    Resau, J.
    Webb, C. P.
    Koochekpour, S.
    Koo, H. M.
    Leppla, S. H.
    Woude, G. F. V.

  2. Author Address

    Van Andel Res Inst, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA. Van Andel Res Inst, Grand Rapids, MI 49503 USA. NCI, Frederick Canc Res & Dev Ctr, Adv Biosci Labs Basic Res Program, NIH, Frederick, MD 21702 USA. Natl Inst Dental Craniofacial Res, NIH, Bethesda, MD 20892 USA. Duesbery NS Van Andel Res Inst, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA.
    1. Year: 2001
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 98
    2. 7
    3. Pages: 4089-4094
  4. Type of Article: Article
  1. Abstract:

    Lethal factor is a protease, one component of Bacillus anthracis exotoxin, which cleaves many of the mitogen-activated protein kinase kinases (MEKs). Given the importance of MEK signaling in tumorigenesis, we assessed the effects of anthrax lethal toxin (LeTx) on tumor cells. LeTx was very effective in inhibiting mitogen-activated protein kinase activation in V12 H-ras-transformed NIH 3T3 cells. In vitro, treatment of transformed cells with LeTx caused them to revert to a nontransformed morphology, and inhibited their abilities to form colonies in soft agar and to invade Matrigel without markedly affecting cell proliferation. In vivo, LeTx inhibited growth of ras-transformed cells implanted in athymic nude mice tin some cases causing tumor regression) at concentrations that caused no apparent animal toxicity. Unexpectedly, LeTx also greatly decreased tumor neovascularization. These results demonstrate that LeTx potently inhibits ras-mediated tumor growth and is a potential antitumor therapeutic.

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