1. The bortezomib-induced mitochondrial damage is mediated by accumulation of active protein kinase C-δ
- Author
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Jihua Liu, Ray M. Lee, David Durrant, and Hung-Sheng Yang
- Subjects
Proteasome Endopeptidase Complex ,Biophysics ,Antineoplastic Agents ,Apoptosis ,Mitochondrion ,Biochemistry ,Bortezomib ,chemistry.chemical_compound ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Benzopyrans ,Protease Inhibitors ,cardiovascular diseases ,Enzyme Inhibitors ,neoplasms ,Molecular Biology ,Protein Kinase C ,Protein kinase C ,Caspase ,biology ,Kinase ,Acetophenones ,U937 Cells ,Cell Biology ,Boronic Acids ,Molecular biology ,Peptide Fragments ,Mitochondria ,Protein Kinase C-delta ,chemistry ,Proteasome ,Pyrazines ,biology.protein ,Rottlerin ,Peptide Hydrolases ,medicine.drug - Abstract
Bortezomib (PS-341) is an inhibitor of the S26 proteasome. Bortezomib induces mitochondrial damage but the exact mechanism remains unclear. We studied PKC-delta, a kinase that is regulated by proteasome degradation and translocates to mitochondria in apoptosis, and examined whether PKC-delta could be a potential mediator of bortezomib-induced mitochondrial damage. Co-incubation of bortezomib with a PKC-delta inhibitor, rottlerin, suppressed bortezomib-induced apoptosis in U937 cells. Western analysis of U937 cells treated with bortezomib revealed accumulation of full-length PKC-delta in the first 4 h. By 16 h an active catalytic fragment of PKC-delta accumulated in mitochondria. The cleavage of PKC-delta after bortezomib treatment was mediated by caspases, because a pan-caspase inhibitor BAF prevented the appearance of the active fragment of PKC-delta. These findings indicate that accumulation of the active PKC-delta fragment in mitochondria is responsible for bortezomib-induced mitochondrial damage.
- Published
- 2004
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