Document Detail


Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer.
MedLine Citation:
PMID:  19391138     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Clusterin (CLU) is a multivalent glycoprotein with ubiquitous tissue distribution. To address the possible differential functional roles assumed by different isoforms of CLU in the progression of human ovarian cancer, we constructed 2 human ovarian cancer cell models that represent examples of contradistinctive CLU expression levels. One is constitutively overexpressing different clusterin isoforms in SKOV3 cells by transfection of the 3 different expression vectors, another is silencing the intrinsically expressing clusterin in cisplatin-resistant human A2780-cis(CP70) tumor cells with the usage of shRNA-mediated CLU gene silencing. Then, the different cellular localization, biological effects, and functional roles played in tumor progression and drug resistances were studied. We found that (i) in the distinct cellular contexts of human ovarian carcinoma SKOV3 and CP70 cells assayed, sCLU is a central molecule in cell homeostasis that functions as a cytoprotective protein, whereas nCLU is proapoptotic; (ii) In SKOV3 cells, nuclear localization of the truncated CLU is NLS dependent, without which the pnCLU protein was sequestrated in cytoplasm to prevent cytotoxicity. (iii) sCLU plays a significant role in the development of the chemoresistance phenotype in ovarian cancer cells. Moreover, with the CLU-specific shRNA oligonucleotides, we successfully sensitized cells for chemotherapy, and inhibited cells' proliferation, migration and invasion. Collectively, our results reveal that, CLU gene expression might play a crucial role in ovarian cancer progression, adaptation and eventual resistance to chemotherapy through differential processing of CLU isoforms. Specifically, sCLU as an antiapoptotic protein, upregulated in an adaptive cell-survival manner by chemotherapy, confers resistance to various cell-death triggers.
Authors:
Li Wei; Tao Xue; Jian Wang; Biliang Chen; Yingfeng Lei; Yanhong Huang; Hongying Wang; Xiaoyan Xin
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  125     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-06-22     Completed Date:  2009-08-04     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  791-806     Citation Subset:  IM    
Affiliation:
Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, People's Republic of China.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Blotting, Western
Cell Cycle / drug effects
Cell Movement / drug effects
Cell Proliferation / drug effects
Cisplatin / therapeutic use
Clusterin / physiology*
Disease Progression
Drug Resistance, Neoplasm*
Female
Humans
Neoplasm Metastasis
Ovarian Neoplasms / drug therapy,  metabolism*,  pathology
Protein Isoforms
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Subcellular Fractions
Transfection
Tumor Cells, Cultured
Tumor Stem Cell Assay
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CLU protein, human; 0/Clusterin; 0/Protein Isoforms; 0/RNA, Messenger; 0/RNA, Small Interfering; 15663-27-1/Cisplatin

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