| Mu-calpain activation in beta-lapachone-mediated apoptosis. | |
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MedLine Citation:
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PMID: 12750552 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Beta-lapachone (beta-Lap) triggers apoptosis in a number of human breast and prostate cancer cell lines through a unique apoptotic pathway that is dependent upon NQO1, a two-electron reductase. Recently, our laboratory showed that beta-lap-exposed MCF-7 cells exhibited an early increase in intracellular cytosolic Ca(2+) from endoplasmic reticulum stores, and that BAPTA-AM (an intracellular Ca(2+) chelator) blocked these early increases and partially inhibited all aspects of beta-lap-induced apoptosis. We now show that exposure of NQO1-expressing breast cancer cells to beta-lap stimulates a unique proteolytic apoptotic pathway involving mu-calpain activation. No apparent activation of m-calpain was noted. Upon activation, mu-calpain translocated to the nucleus concomitant with specific nuclear proteolytic events. Apoptotic responses in beta-lap-exposed NQO1-expressing cells were significantly delayed and survival enhanced by exogenous over-expression of calpastatin, a natural inhibitor of mu- and m-calpains. Furthermore, purified mu-calpain cleaved PARP to a unique fragment (approximately 60 kDa), not previously reported for calpains. We provide evidence that beta-lap-induced, mu-calpain-stimulated apoptosis does not involve any known apoptotic caspases; the activated fragments of caspases were not observed after beta-lap exposures, nor were there any changes in the pro-enzyme forms as measured by Western blot analyses. The ability of beta-lap to trigger an apparently novel, p53-independent, calpain-mediated apoptotic cell death further support the development of this drug for improved breast cancer therapy. |
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Authors:
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Colleen Tagliarino; John J Pink; Kathryn E Reinicke; Sara M Simmers; Shelly M Wuerzberger-Davis; David A Boothman |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Cancer biology & therapy Volume: 2 ISSN: 1538-4047 ISO Abbreviation: Cancer Biol. Ther. Publication Date: 2003 Mar-Apr |
Date Detail:
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Created Date: 2003-05-16 Completed Date: 2003-10-16 Revised Date: 2012-05-28 |
Medline Journal Info:
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Nlm Unique ID: 101137842 Medline TA: Cancer Biol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 141-52 Citation Subset: IM |
Affiliation:
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Departments of Radiation Oncology and Pharmacology,Case Western Reserve University, Cleveland, Ohio 44106-4942, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antibiotics, Antineoplastic
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pharmacology* Apoptosis / drug effects* Blotting, Western Breast Neoplasms / drug therapy, metabolism*, pathology* Calcium / metabolism Calcium-Binding Proteins / pharmacology Calpain / antagonists & inhibitors, metabolism* Caspases / metabolism Cell Nucleus / metabolism Colony-Forming Units Assay Cysteine Proteinase Inhibitors / pharmacology Cytosol / metabolism Enzyme Activation Female Humans In Situ Nick-End Labeling Microscopy, Confocal NAD(P)H Dehydrogenase (Quinone) / genetics, metabolism, pharmacology* Naphthoquinones / pharmacology* Poly(ADP-ribose) Polymerases / metabolism Protein Transport Tumor Cells, Cultured Tumor Suppressor Protein p53 / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Calcium-Binding Proteins; 0/Cysteine Proteinase Inhibitors; 0/Naphthoquinones; 0/Tumor Suppressor Protein p53; 4707-32-8/beta-lapachone; 7440-70-2/Calcium; 79079-11-1/calpastatin; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone); EC 1.6.5.2/NQO1 protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Calpain; EC 3.4.22.-/Caspases; EC 3.4.22.-/m-calpain; EC 3.4.22.-/mu-calpain |
| Comments/Corrections | |
Comment In:
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Cancer Biol Ther. 2003 Mar-Apr;2(2):153-4
[PMID:
12750553
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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