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Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex

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Title Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex
 
Creator Sen, N
Banerjee, B
Das, BB
Ganguly, A
Sen, T
Pramanik, S
Mukhopadhyay, S
Majumder, HK
 
Subject Biochemistry & Molecular Biology; Cell Biology
 
Description Protein kinase C (PKC) is an important constituent of the signaling pathways involved in apoptosis. We report here that like staurosporine, withaferin A is a potent inhibitor of PKC. In Leishmania donovani, the inhibition of PKC by withaferin A causes depolarization of Delta Psi(m) and generates ROS inside cells. Loss of Delta Psi(m) leads to the release of cytochrome c into the cytosol and subsequently activates caspase-like proteases and oligonucleosomal DNA cleavage. Moreover, in treated cells, oxidative DNA lesions facilitate the stabilization of topoisomerase I-mediated cleavable complexes, which also contribute to DNA fragmentation. However, withaferin A and staurosporine cannot induce cleavable complex formation in vitro with recombinant topoisomerase I nor with nuclear extracts from control cells. Taken together, our results indicate that inhibition of PKC by withaferin A is a central event for the induction of apoptosis and that the stabilization of topoisomerase I-DNA complex is necessary to amplify apoptotic process.
 
Publisher NATURE PUBLISHING GROUPLONDONMACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
 
Date 2011-09-20T12:12:41Z
2011-09-20T12:12:41Z
2007
 
Type Article
 
Identifier CELL DEATH AND DIFFERENTIATION
1350-9047
http://hdl.handle.net/123456789/14382
 
Language English