The bortezomib-induced mitochondrial damage is mediated by accumulation of active protein kinase C-delta.
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.
Durrant
David
D
Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
Liu
Jihua
J
Yang
Hung-Sheng
HS
Lee
Ray M
RM
D000098:Acetophenones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D010446:Peptide Fragments / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D011719:Pyrazines / Q000494:pharmacology*; D020298:U937 Cells
D000098:Acetophenones; D000970:Antineoplastic Agents; D001578:Benzopyrans; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; C085746:rottlerin; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease