Anthrax Research Today is a free monthly online journal that collates and summarizes the latest research about Anthrax, including details on bacillus anthracis, contagiousness, exposure, effects. | ||||||||
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Cytotoxicity of the matrix metalloproteinase-activated anthrax lethal toxin is dependent on gelatinase expression and B-RAF status in human melanoma cells.Alfano RW, Leppla SH, Liu S, Bugge TH, Herlyn M, Smalley KS, Bromberg-White JL, Duesbery NS, Frankel AE Scott & White Cancer Research Institute, 5701 South Airport Road, Temple, TX 76502. afrankel@swmail.sw.org. Anthrax lethal toxin (LeTx) shows potent mitogen-activated protein kinase pathway inhibition and apoptosis in melanoma cells that harbor the activating V600E B-RAF mutation. LeTx is composed of two proteins, protective antigen and lethal factor. Uptake of the toxin into cells is dependent on proteolytic activation of protective antigen by the ubiquitously expressed furin or furin-like proteases. To circumvent nonspecific LeTx activation, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. Here, we have shown that the toxicity of this matrix metalloproteinase (MMP)-activated LeTx is dependent on host cell surface MMP-2 and MMP-9 activity as well as the presence of the activating V600E B-RAF mutation, making this toxin dual specific. This additional layer of tumor cell specificity would potentially decrease systemic toxicity from the reduction of nonspecific toxin activation while retaining antitumor efficacy in patients with V600E B-RAF melanomas. Moreover, our results indicate that cell surface-associated gelatinase expression can be used to predict sensitivity among V600E B-RAF melanomas. This finding will aid in the better selection of patients that will potentially respond to MMP-activated LeTx therapy. [Mol Cancer Ther 2008;7(5):1218-26]. Published 16 May 2008 in Mol Cancer Ther, 7(5): 1218-26.
© 2005-2008 Anthrax Research Today. All Rights Reserved. |
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