Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinase.
Lethal factor, the principal virulence factor of Bacillus anthracis, inhibits mitogen-activated protein kinase (MAPK) signaling by proteolytically cleaving MAPK kinases. Edema factor, another component of anthrax toxin, is an adenylate cyclase, which increases intracellular cAMP. Inhibition of MAPK signaling with either anthrax lethal toxin (LeTx) or small molecule MAPK kinase inhibitors triggers apoptosis in human melanoma cells. Normal melanocytes do not undergo apoptosis in response to MAPK inhibition but arrest in the G1 phase of the cell cycle. Importantly, in vivo treatment of human melanoma xenograft tumors in athymic nude mice with LeTx results in significant or complete tumor regression without apparent side effects, suggesting that inhibiting the MAPK signaling pathway may be a useful strategy for treating melanoma. Additionally, interrupting MAPK signaling with LeTx and elevating cAMP with anthrax edema toxin in both melanoma cells and melanocytes lead to dramatic melanin production, perhaps explaining the formation of blackened eschars in cutaneous anthrax.
Koo
Han-Mo
HM
Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA. hanmo.koo@vai.org
VanBrocklin
Matt
M
McWilliams
Mary Jane
MJ
Leppla
Stephan H
SH
Duesbery
Nicholas S
NS
Vande Woude
George F
GF
D000262:Adenylyl Cyclases / Q000494:pharmacology; D000818:Animals; D000942:Antigens, Bacterial; D017209:Apoptosis; D001408:Bacillus anthracis; D001427:Bacterial Toxins / Q000494:pharmacology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma; D008546:Melanoma, Experimental / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008543:Melanins; C030325:anthrax toxin; D020929:Mitogen-Activated Protein Kinase Kinases; D000262:Adenylyl Cyclases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one