Abstract:
Anthrax lethal toxin is an A-B toxin consisting of protective antigen (PrAg), the cell binding and translocation domain, and lethal factor (LF), the catalytic domain, which cleaves all mitogen-activated protein/extracellular regulated kinase kinases (MEKs), leading to the inhibition of the MAPK pathway. Anthrax lethal toxin has been extensively studied for its antitumor effect and showed potency against the majority of acute myeloid leukemia cell lines. In addition to that, previous data have shown that autophagy is activated in most AML cell lines. In this study we investigate the effect of anthrax lethal toxin on the downstream effectors of
MEK in the Ras-Raf-MEK-ERK pathway, investigate the effect of MEK inhibition on the downregulation of ERK and try to explore the mechanism underlying autophagy which plays a protective role at later time points, as previously shown. This study aims to explain the difference in susceptibility of different AML cell lines. Flow cytometry analysis of downstream effectors of MEK showed decrease in phosphorylation of ERK and its downstream effectors only at early time points in sensitive cell lines.
Whereas this pattern was not observed in resistant cell lines that showed a
constant level of activation up to 120 hours after treatment. Finally, the effect on autophagy is to be more studied by testing for the expression of more proteins involved.
