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Sen N, Banerjee B, Das BB, Ganguly A, Sen T, Pramanik S, Mukhopadhyay S,
Majumder HK.
Cell Death Differ. 2007 Feb;14(2):358-67. Epub 2006 Jul 14
Apoptosis is induced in leishmanial cells by a novel protein
kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase
I-DNA complex.
Division of Infectious Diseases, Indian Institute of Chemical Biology, 4,
Raja SC Mullick Road, Kolkata 700 032, India.
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 DeltaPsim and generates ROS inside cells.
Loss of DeltaPsim 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.
PMID: 16841091
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