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

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 eff ects of anthrax lethal toxin (LeTx) on tumor cells. LeTx was very effective in inhibiting mitogen-activated protein kinase activation in V12 H-ras-tra nsformed NIH 3T3 cells. In vitro, treatment of transformed cells with LeTx caused them to revert to a nontransformed morphology, and inhibited their a bilities to form colonies in soft agar and to invade Matrigel without marke dly affecting cell proliferation. In vivo, LeTx inhibited growth of ras-tra nsformed cells implanted in athymic nude mice tin some cases causing tumor regression) at concentrations that caused no apparent animal toxicity. Unex pectedly, LeTx also greatly decreased tumor neovascularization. These resul ts demonstrate that LeTx potently inhibits ras-mediated tumor growth and is a potential antitumor therapeutic.