Document Detail


Lysosomal destabilization and cathepsin B contributes for cytochrome c release and caspase activation in embelin-induced apoptosis.
MedLine Citation:
PMID:  19943316     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
XIAP is an important antiapoptotic protein capable of conferring resistance to cancer cells. Embelin, the small molecular inhibitor of XIAP, possesses wide spectrum of biological activities with strong inhibition of nuclear factor kappa B and downstream antiapoptotic genes. However, the mechanism of its cell death induction is not known. Our studies using colon cancer cells lacking p53 and Bax suggest that both lysosomes and mitochondria are prominent targets of embelin-induced cell death. Embelin induced cell-cycle arrest in G(1) phase through p21, downstream of p53. In the absence of p21, the cells are sensitized to death in a Bax-dependent manner. The loss of mitochondrial membrane potential induced by embelin was independent of Bax and p53, but lysosomal integrity loss was strongly influenced by the presence of p53 but not by Bax. Lysosomal role was further substantiated by enhanced cathepsin B activity noticed in embelin-treated cells. p53-dependent lysosomal destabilization and cathepsin B activation contribute for increased sensitivity of p21-deficient cells to embelin with enhanced caspase 9 and caspase 3 activation. Cathepsin B inhibitor reduced cell death and cytochrome c release in embelin-treated cells indicating lysosomal pathway as the upstream of mitochondrial death signaling. Deficiency of cell-cycle arrest machinery renders cells more sensitive to embelin with enhanced lysosomal destabilization and caspase processing emphasizing its potential therapeutic importance to address clinical drug resistance.
Authors:
Beena Joy; Rajeeve Sivadasan; Emilia Abraham T; Mohan John; Praveen K Sobhan; Mahendra Seervi; Santhoshkumar T R
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular carcinogenesis     Volume:  49     ISSN:  1098-2744     ISO Abbreviation:  Mol. Carcinog.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-01     Completed Date:  2010-05-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8811105     Medline TA:  Mol Carcinog     Country:  United States    
Other Details:
Languages:  eng     Pagination:  324-36     Citation Subset:  IM    
Affiliation:
Agroprocessing and Natural Product Division, National Institute for Interdisciplinary Science & Technology, Thiruvananthapuram, Kerala, India.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*,  physiology
Benzoquinones / chemistry,  pharmacology*
Caspases / genetics,  metabolism
Cathepsin B / metabolism*
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cytochromes c / metabolism*
Dose-Response Relationship, Drug
Enzyme Activation
HCT116 Cells
Humans
Lysosomes / metabolism*
Membrane Potential, Mitochondrial / drug effects
Mitochondria / metabolism,  physiology
Tumor Suppressor Protein p53 / metabolism
bcl-2-Associated X Protein / genetics
Chemical
Reg. No./Substance:
0/Benzoquinones; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; 550-24-3/embelin; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspases; EC 3.4.22.1/Cathepsin B

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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