Document Detail


Calpain-mediated processing of p53-associated parkin-like cytoplasmic protein (PARC) affects chemosensitivity of human ovarian cancer cells by promoting p53 subcellular trafficking.
MedLine Citation:
PMID:  22117079     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Resistance to cisplatin (CDDP)-based therapy is a major hurdle to the successful treatment of human ovarian cancer (OVCA), and the chemoresistant phenotype in OVCA cells is associated with Akt-attenuated p53-mediated apoptosis. Pro-apoptotic functions of p53 involve both transcription-dependent and -independent signaling pathways, and dysfunctional localization and/or inactivation of p53 contribute to the development of chemoresistance. PARC is a cytoplasmic protein regulating p53 subcellular localization and subsequent function. Little is known about the molecular mechanisms regulating PARC. Although PARC contains putative caspase-3 cleavage sites, and CDDP is known to induce the activation of caspases and calpains and induce proteasomal degradation of anti-apoptotic proteins, if and how PARC is regulated by CDDP in OVCA are unknown. Here, we present evidence that CDDP promotes calpain-mediated PARC down-regulation, mitochondrial and nuclear p53 accumulation, and apoptosis in chemosensitive but not resistant OVCA cells. Inhibition of Akt is required to sensitize chemoresistant cells to CDDP in a p53-dependent manner, an effect enhanced by PARC down-regulation. CDDP-induced PARC down-regulation is reversible by inhibition of calpain but not of caspases or the 26 S proteasome. Furthermore, in vitro experiments confirm the ability of calpain in mediating Ca(2+)-dependent PARC down-regulation. The role of Ca(2+) in PARC down-regulation was further confirmed as ionomycin-induced PARC down-regulation in both chemosensitive and chemoresistant ovarian cancer cells. The data presented here implicate the regulation of p53 subcellular localization and apoptosis by PARC as a contributing factor in CDDP resistance in OVCA cells and Ca(2+)/calpain in PARC post-translational processing and chemosensitivity.
Authors:
Michael G Woo; Kai Xue; Jiayin Liu; Heidi McBride; Benjamin K Tsang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-11-23
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-03-25     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3963-75     Citation Subset:  IM    
Affiliation:
Reproductive Biology Unit and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Apoptosis / drug effects,  genetics
Calcium / metabolism
Calcium Ionophores / pharmacology
Calpain / genetics,  metabolism*
Carrier Proteins / genetics,  metabolism*
Caspase 3 / genetics,  metabolism
Cell Line, Tumor
Cisplatin / pharmacology
Down-Regulation / drug effects,  genetics
Drug Resistance, Neoplasm*
Enzyme Activation / drug effects,  genetics
Female
Gene Expression Regulation, Neoplastic*
Humans
Ionomycin / pharmacology
Ovarian Neoplasms / drug therapy,  genetics,  metabolism*,  pathology
Proteasome Endopeptidase Complex / genetics,  metabolism
Protein Processing, Post-Translational*
Protein Transport / drug effects
Tumor Suppressor Protein p53 / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
MOP-15691//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Calcium Ionophores; 0/Carrier Proteins; 0/H7-AP1 protein, human; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 15663-27-1/Cisplatin; 56092-81-0/Ionomycin; 7440-70-2/Calcium; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Calpain; EC 3.4.22.-/Caspase 3; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 3.4.99.-/ATP dependent 26S protease
Comments/Corrections

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