Down-regulation of caspase-2 by rottlerin via protein kinase C-delta-independent pathway.
Protein kinase C-delta (PKC delta) plays an important role in DNA damage-induced apoptosis. We have previously shown that the PKC delta 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 delta 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 delta-independent but ubiquitin proteasome-mediated pathway. Furthermore, down-regulation of caspase-2 by rottlerin can explain its antiapoptotic function during DNA damage-induced apoptosis.
Basu
Alakananda
A
Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. abasu@hsc.unt.edu
Adkins
Brett
B
Basu
Chandreyi
C
D000098:Acetophenones / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D053143:Caspase 2 / Q000235:genetics*; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics*; D004249:DNA Damage; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D010051:Ovarian Neoplasms; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D025801:Ubiquitin; C085746:rottlerin; D051745:Protein Kinase C-delta; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex