| Protein kinase Cδ and caspase-3 modulate TRAIL-induced apoptosis in breast tumor cells. | |
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MedLine Citation:
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PMID: 20665667 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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This report describes that protein kinase C delta (PKCδ) overexpression prevents TRAIL-induced apoptosis in breast tumor cells; however, the regulatory mechanism(s) involved in this phenomenon is(are) incompletely understood. In this study, we have shown that TRAIL-induced apoptosis was significantly inhibited in PKCδ overexpressing MCF-7 (MCF7/PKCδ) cells. Our data reveal that PKCδ inhibits caspase-8 activation, a first step in TRAIL-induced apoptosis, thus preventing TRAIL-induced apoptosis. Inhibition of PKCδ using rottlerin or PKCδ siRNA reverses the inhibitory effect of PKCδ on caspase-8 activation leading to TRAIL-induced apoptosis. To determine if caspase-3-induced PKCδ cleavage reverses its inhibition on caspase-8, we developed stable cell lines that either expresses wild-type PKCδ (MCF-7/cas-3/PKCδ) or caspase-3 cleavage-resistant PKCδ mutant (MCF-7/cas-3/PKCδ mut) utilizing MCF-7 cells expressing caspase-3. Cells that overexpress caspase-3 cleavage-resistant PKCδ mutant (MCF-7/cas-3/PKCδmut) significantly inhibited TRAIL-induced apoptosis when compared to wild-type PKCδ (MCF-7/cas-3/PKCδ) expressing cells. In MCF-7/cas-3/PKCδmut cells, TRAIL-induced caspase-8 activation was blocked leading to inhibition of apoptosis when compared to wild-type PKCδ (MCF-7/cas-3/PKCδ) expressing cells. Together, these results strongly suggest that overexpression of PKCδ inhibits caspase-8 activation leading to inhibition of TRAIL-induced apoptosis and its inhibition by rottlerin, siRNA, or cleavage by caspase-3 sensitizes cells to TRAIL-induced apoptosis. Clinically, PKCδ overexpressing tumors can be treated with a combination of PKCδ inhibitor(s) and TRAIL as a new treatment strategy. |
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Authors:
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Shuping Yin; Seema Sethi; Kaladhar B Reddy |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Journal of cellular biochemistry Volume: 111 ISSN: 1097-4644 ISO Abbreviation: J. Cell. Biochem. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-27 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8205768 Medline TA: J Cell Biochem Country: United States |
Other Details:
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Languages: eng Pagination: 979-87 Citation Subset: IM |
Affiliation:
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Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, Michigan 48201, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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R01 CA 118089/CA/NCI NIH HHS |
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