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 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 (in 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.
Duesbery
N S
NS
Van Andel Research Institute, 333 Bostwick Avenue, NE, Grand Rapids, MI 49503, USA. duesbery@vai.org
Resau
J
J
Webb
C P
CP
Koochekpour
S
S
Koo
H M
HM
Leppla
S H
SH
Vande Woude
G F
GF
D016475:3T3 Cells; D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000494:pharmacology* / Q000627:therapeutic use; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004195:Disease Models, Animal; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D018631:ras Proteins / Q000502:physiology
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D020929:Mitogen-Activated Protein Kinase Kinases; D010447:Peptide Hydrolases; D018631:ras Proteins