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Down-regulation of Caspase-2 by Rottlerin via Protein Kinase C-–Independent Pathway

Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas

Requests for reprints: Alakananda Basu, Department of Molecular Biology & Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107. Phone: 817-735-2487; Fax: 817-735-2118; E-mail: abasu{at}hsc.unt.edu.

Key Words: caspase-2 • rottlerin • PKC • cisplatin • apoptosis

Protein kinase C- (PKC) plays an important role in DNA damage–induced apoptosis. We have previously shown that the PKC inhibitor rottlerin protects against cisplatin-induced apoptosis acting upstream of caspase-9. In the present study, we have investigated if rottlerin regulates caspase-2 activation. Knockdown of caspase-2 by siRNA inhibited processing of apical caspase-9 and caspase-8, whereas depletion of caspase-9 had little effect on caspase-2 processing. Rottlerin inhibited activation and processing of caspase-9 and caspase-8 and cleavage of poly(ADP)ribose polymerase. We made a novel observation that rottlerin induced down-regulation of caspase-2 but not of caspase-3, caspase-7, caspase-8, or caspase-9. Pharmacologic inhibitors of PKC, such as Gö 6983 and bisindolylmaleimide, or depletion of PKC by siRNA had no effect on the down-regulation of caspase-2 by rottlerin. The proteasome inhibitor MG132 reversed caspase-2 down-regulation by rottlerin, whereas calpain inhibitor had no effect. These results suggest that rottlerin induces down-regulation of caspase-2 via PKC-independent but ubiquitin proteasome–mediated pathway. Furthermore, down-regulation of caspase-2 by rottlerin can explain its antiapoptotic function during DNA damage–induced apoptosis. [Cancer Res 2008;68(8):2795–802]

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