| Molecular mechanism of chemoresistance by astrocyte elevated gene-1. | |
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MedLine Citation:
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PMID: 20388796 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Our recent findings show that astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human hepatocellular carcinoma (HCC) samples, and AEG-1 plays a central role in regulating development and progression of HCC. In the present study, we elucidate a molecular mechanism of AEG-1-induced chemoresistance, an important characteristic of aggressive cancers. AEG-1 increases the expression of multidrug resistance gene 1 (MDR1) protein, resulting in increased efflux and decreased accumulation of doxorubicin, promoting doxorubicin resistance. Suppression of MDR1 by small interfering RNA or chemical reagents, or inhibition of AEG-1 or a combination of both genes, significantly increases in vitro sensitivity to doxorubicin. In nude mice xenograft studies, a lentivirus expressing AEG-1 short hairpin RNA, in combination with doxorubicin, profoundly inhibited growth of aggressive human HCC cells compared with either agent alone. We document that although AEG-1 does not affect MDR1 gene transcription, it facilitates association of MDR1 mRNA to polysomes, resulting in increased translation, and AEG-1 also inhibits ubiquitination and subsequent proteasome-mediated degradation of MDR1 protein. This study is the first documentation of a unique aspect of AEG-1 function (i.e., translational and posttranslational regulation of proteins). Inhibition of AEG-1 might provide a means of more effectively using chemotherapy to treat HCC, which displays inherent chemoresistance with aggressive pathology. |
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Authors:
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Byoung Kwon Yoo; Dong Chen; Zhao-Zhong Su; Rachel Gredler; Jinsang Yoo; Khalid Shah; Paul B Fisher; Devanand Sarkar |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-04-13 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-16 Completed Date: 2010-04-28 Revised Date: 2012-04-04 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3249-58 Citation Subset: IM |
Copyright Information:
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(c) 2010 AACR. |
Affiliation:
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Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, and VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carcinoma, Hepatocellular / enzymology* Cell Adhesion Molecules / biosynthesis*, physiology* Cell Line, Tumor Doxorubicin / pharmacology Gene Expression Regulation, Neoplastic* Humans Lentivirus / genetics Liver Neoplasms / enzymology* Mice Mice, Nude Neoplasm Transplantation P-Glycoprotein / metabolism RNA, Messenger / metabolism RNA, Small Interfering / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA035675/CA/NCI NIH HHS; R01 CA035675-22/CA/NCI NIH HHS; R01 CA134721/CA/NCI NIH HHS; R01 CA134721-01A1/CA/NCI NIH HHS; R01 CA134721-04/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ABCB1 protein, human; 0/Cell Adhesion Molecules; 0/MTDH protein, human; 0/P-Glycoprotein; 0/RNA, Messenger; 0/RNA, Small Interfering; 23214-92-8/Doxorubicin |
| Comments/Corrections | |
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