Rocha, S., Soengas, M. S., Lowe, S. W., Glanzmann, C., Fabbro, D., Winterhalter, K., Bodis, S., Pruschy, M. (September 2000) Protein kinase C inhibitor and irradiation-induced apoptosis: Relevance of the cytochrome c-mediated caspase-9 death pathway. Cell Growth & Differentiation, 11 (9). pp. 491-499. ISSN 1044-9523
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Abstract
Caspases are a family of cysteine proteases that constitute the apoptotic cell death machinery, We report the importance of the cytochrome c-mediated caspase-9 death pathway for radiosensitization by the protein kinase C (PKC) inhibitors staurosporine (STP) and PKC-412. In our genetically defined tumor cells, treatment with low doses of STP or the conventional PKC-specific inhibitor PKC-412 in combination with irradiation (5 Gy) potently reduced viability, enhanced mitochondrial cytochrome c release into the cytosol, and specifically stimulated the initiator caspase-9. Whereas treatment with each agent alone had a minimal effect, combined treatment resulted in enhanced caspase-3 activation. This was prevented by broad-range and specific caspase-9 inhibitors and absent in caspase-9-deficient cells. The tumor suppressor p53 was required for apoptosis induction by combined treatment but was dispensable for dose-dependent STP-induced caspase activation. These results demonstrate the requirement for an intact caspase-9 pathway for apoptosis-based radiosensitization by PKC inhibitors and show that STP induces apoptosis independent of p53.
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