| G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells. | |
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MedLine Citation:
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PMID: 19996277 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Agents stabilizing G-quadruplexes have the potential to destroy the functional structure of telomere and could therefore act as antitumor agents. We previously reported that SYUIQ-5 could stabilize G-quadruplex, induce senescence, and inhibit c-myc gene promoter activity. In this study, we showed that SYUIQ-5 inhibited proliferation of CNE2 and HeLa cancer cells, triggered a rapid and potent telomere DNA damage response characterized by the formation of telomeric foci gamma-H2AX, and obviously induced autophagy with the features of increased LC3-II and a punctuated pattern of YFP-LC3 fluorescence. These phenomena may primarily depend on the delocalization of TRF2 from telomere, which was further degraded by proteasomes. Furthermore, overexpression of TRF2 inhibited SYUIQ-5-induced gamma-H2AX expression. Also, ATM was activated following SYUIQ-5 treatment. The pretreatment with ATM inhibitor ku55933 and ATM siRNA effectively reduced the production of gamma-H2AX and LC3-II. ATM knockdown partially antagonized the anticancer effects of SYUIQ-5. Moreover, inhibition of autophagy by short hairpin RNA against the autophagy-related gene ATG5 attenuated the cytotoxicity of SYUIQ-5. These results indicated that SYUIQ-5 triggered potent telomere damage through TRF2 delocalization from telomeres, and eventually induced autophagic cell death in cancer cells. Our findings exhibit a novel mechanism that is responsible for the antitumor effects of SYUIQ-5. |
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Authors:
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Wen-Jun Zhou; Rong Deng; Xiao-Yue Zhang; Gong-Kan Feng; Lian-Quan Gu; Xiao-Feng Zhu |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 8 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-12-16 Completed Date: 2010-03-24 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 3203-13 Citation Subset: IM |
Affiliation:
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State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou 510060, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Autophagy
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drug effects* Cell Cycle Proteins / genetics, metabolism Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects DNA Damage DNA-Binding Proteins / genetics, metabolism Diamines / pharmacology* G-Quadruplexes / drug effects Hela Cells Histones / genetics, metabolism Humans Immunoblotting Ligands Luminescent Proteins / genetics, metabolism Microscopy, Confocal Microtubule-Associated Proteins / genetics, metabolism Protein-Serine-Threonine Kinases / genetics, metabolism Quinolines / pharmacology* RNA Interference Telomere / drug effects*, genetics, metabolism Telomeric Repeat Binding Protein 2 / genetics, metabolism* Tumor Suppressor Proteins / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/ATG5 protein, human; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Diamines; 0/H2AFX protein, human; 0/Histones; 0/Ligands; 0/Luminescent Proteins; 0/Microtubule-Associated Proteins; 0/N'-(10H-indolo(3,2-b)quinolin-11-yl)-N,N-dimethylpropane-1,3-diamine; 0/Quinolines; 0/Telomeric Repeat Binding Protein 2; 0/Tumor Suppressor Proteins; 0/light chain 3, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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