| Securinine induces p73-dependent apoptosis preferentially in p53-deficient colon cancer cells. | |
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MedLine Citation:
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PMID: 20133503 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The identification of agents that preferentially kill cancer cells while protecting normal cells offers the potential to overcome toxicities found in many existing chemotherapeutic agents. Because p53 is frequently inactivated in cancer, agents that preferentially kill p53-null cells and protect wild-type p53-expressing cells are highly desirable chemotherapeutic agents. By using pairs of isogenic colon cancer cell lines that differ only in p53 expression (RKO and HCT116), securinine was found to exhibit these properties. Securinine (30 microM) induces apoptosis in 73% of p53-null HCT116 cells (LD(50) 17.5 microM) as opposed to 17.6% of HCT116 parental cells (LD(50) 50 microM) at 72 h after treatment. The mechanism of securinine-mediated death in p53-deficient cells involves the induction of the p53 family member, p73. Interestingly, the proapoptotic protein p73 is down-regulated in colon cancer cells expressing p53. This differential regulation of p73 in a p53-dependent fashion reveals a novel pathway for preferentially targeting cancer cells. In contrast to p53-deficient cells, cells expressing p53 are protected from cell death through the p53-mediated up-regulation of p21. These studies reveal a novel approach to specifically target colon cancer cells lacking p53 as well as identify a novel clinically relevant pathway to selectively induce p73 in p53-null cells. |
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Authors:
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Sonia Rana; Kalpana Gupta; Jose Gomez; Shigemi Matsuyama; Amitabha Chakrabarti; Munna L Agarwal; Anju Agarwal; Mukesh K Agarwal; David N Wald |
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Publication Detail:
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Type: Journal Article Date: 2010-02-04 |
Journal Detail:
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Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 24 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-02 Completed Date: 2010-07-21 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 2126-34 Citation Subset: IM |
Affiliation:
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Invenio Therapeutics, Cleveland, Ohio, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Azepines / pharmacology* Blotting, Western Caspases / antagonists & inhibitors, metabolism Cell Adhesion / drug effects Cell Cycle / drug effects Cell Proliferation / drug effects Colonic Neoplasms / drug therapy, metabolism*, pathology* DNA Damage / drug effects DNA-Binding Proteins / genetics, metabolism* Heterocyclic Compounds with 4 or More Rings / pharmacology Humans Lactones / pharmacology* Nuclear Proteins / genetics, metabolism* Piperidines / pharmacology* RNA, Messenger / genetics, metabolism Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Tumor Suppressor Protein p53 / genetics, metabolism* Tumor Suppressor Proteins / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Azepines; 0/DNA-Binding Proteins; 0/Heterocyclic Compounds with 4 or More Rings; 0/Lactones; 0/Nuclear Proteins; 0/Piperidines; 0/RNA, Messenger; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 0/tumor suppressor protein p73; 5610-40-2/securinine; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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