Document Detail


HIV-Tat-mediated delivery of an LPTS functional fragment inhibits telomerase activity and tumorigenicity of hepatoma cells.
MedLine Citation:
PMID:  20816839     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Human liver-related putative tumor suppressor (LPTS) is a gene that encodes a telomerase inhibitory protein that is similar to human Pin2/TRF1-interacting protein. The LPTS protein binds directly to the telomerase catalytic subunit (human telomerase reverse transcriptase) and suppresses telomerase activity. Telomere maintenance and telomerase activity are required for long-term proliferation of cancer cells, so LPTS might be used in anticancer strategies.
METHODS: The carboxy-terminal (functional) fragment of LPTS was fused to the transactivator of transcription of human immunodeficiency virus (Tat)-an 11-amino acid peptide that translocates across the cell membrane; the TAT-fused C-terminal of LPTS (TAT-LPTS-LC) was purified and transduced into cells. Telomerase activity was identified by using the telomeric repeat amplification protocol. The effects of the TAT-LPTS-LC protein on cell proliferation and death were evaluated by colorimetric tetrazolium salt and flow cytometry analyses. Tumor growth was analyzed in nude mice.
RESULTS: The purified TAT-LPTS-LC protein was efficiently delivered into the cells, where it suppressed telomerase activity and shortened telomere length. TAT-LPTS-LC inhibited proliferation of telomerase-positive hepatocellular carcinoma BEL-7404 and hepatoblastoma HepG2cells and induced their death; however, it had no effect on telomerase-negative liver cell line L02 and osteosarcoma cell line Saos-2. In mice, tumor formations by BEL-7404 cells were suppressed by TAT-LPTS-LC treatments.
CONCLUSIONS: Transduction of hepatoma cells with a fusion protein that contains the C-terminal, functional fragment of LPTS and human immunodeficiency virus Tat (TAT-LPTS-LC) causes telomere shortening, limits proliferation, and inhibits growth of tumors from these cells in mice. TAT-LPTS-LC inhibits telomerase activity and might be developed as an anticancer agent.
Authors:
Guangming Chen; Liang Da; Hongfei Wang; Ying Xu; Guoyuan Chen; Chengfu Sun; Leiming Wang; Jing Zhao; Fang Zhang; Jian Feng; Yifei Wang; Pierre Tiollais; Tsaiping Li; Mujun Zhao
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-20
Journal Detail:
Title:  Gastroenterology     Volume:  140     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-21     Completed Date:  2011-01-20     Revised Date:  2011-09-26    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  332-43     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
Affiliation:
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carcinoma, Hepatocellular / drug therapy*
Drug Delivery Systems
Humans
Liver Neoplasms / drug therapy*
Mice
Mice, Nude
Recombinant Fusion Proteins / administration & dosage*,  genetics,  metabolism
Telomerase / antagonists & inhibitors*
Tumor Suppressor Proteins / administration & dosage*,  genetics,  metabolism
tat Gene Products, Human Immunodeficiency Virus / administration & dosage*,  genetics,  metabolism
Chemical
Reg. No./Substance:
0/PINX1 protein, human; 0/Recombinant Fusion Proteins; 0/Tumor Suppressor Proteins; 0/tat Gene Products, Human Immunodeficiency Virus; EC 2.7.7.49/Telomerase

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


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