Parent, Nicolas and Scherer, Max and Liebisch, Gerhard and Schmitz, Gerd and Bertrand, Richard (2011) Protein kinase C-delta isoform mediates lysosome labilization in DNA damage-induced apoptosis. INTERNATIONAL JOURNAL OF ONCOLOGY, 38 (2). pp. 313-324. ISSN 1019-6439, 1791-2423
Full text not available from this repository. (Request a copy)Abstract
A lysosomal pathway, characterized by the partial rupture or labilization of lysosomal membranes (LLM) and cathepsin release into the cytosol, is evoked during the early events of 20-S-camptothecin lactone (CPT)-induced apoptosis in human cancer cells, including human histiocytic lymphoma U-937 cells. These lysosomal events begin rapidly and simultaneously with mitochondrial permeabilization and caspase activation within 3 h after drug treatment. Recently, in a comparative proteomics analysis performed on highly-enriched lysosomal extracts, we identified proteins whose translocation to lysosomes correlated with LLM induction after CPT treatment, including protein kinase C-delta (PKC-delta). In this study, we show that the PKC-delta translocation to lysosomes is required for LLM, as silencing its expression with RNA interference or suppressing its activity with the inhibitor, rottlerin, prevents CPT-induced LLM. PKC-delta translocation to lysosomes is associated with lysosomal acidic sphingomyelinase (ASM) phosphorylation and activation, which in turn leads to an increase in ceramide (CER) content in lysosomes. The accumulation of endogenous CER in lysosomes is a critical event for CPT-induced LLM as suppressing PKC-delta or ASM activity reduces both the CPT-mediated CER generation in lysosomes and CPT-induced LLM. These findings reveal a novel mechanism by which PKC-delta mediates ASM phosphorylation/activation and CER accumulation in lysosomes in CPT-induced LLM, rapidly activating the lysosomal pathway of apoptosis after CPT treatment.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TANDEM MASS-SPECTROMETRY; CAMPTOTHECIN-INDUCED APOPTOSIS; CELL-DEATH; MEMBRANE PERMEABILIZATION; ACID SPHINGOMYELINASE; OXIDATIVE STRESS; CANCER-CELLS; CYTOCHROME-C; DEPENDENT MECHANISMS; PHOSPHOLIPASE A(2); apoptosis; camptothecin; lysosome; protein kinase C-delta; sphingolipids; electrospray ionization/tandem mass spectrometry |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Jun 2020 11:12 |
| Last Modified: | 26 Jun 2020 11:12 |
| URI: | https://pred.uni-regensburg.de/id/eprint/21356 |
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