Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Autophagy / drug effects*
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Autophagy-Related Protein 5
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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DNA Damage
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Diamines / pharmacology*
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G-Quadruplexes / drug effects
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HeLa Cells
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Histones / genetics
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Histones / metabolism
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Humans
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Immunoblotting
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Ligands
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Microscopy, Confocal
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Quinolines / pharmacology*
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RNA Interference
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Telomere / drug effects*
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Telomere / genetics
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Telomere / metabolism
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Telomeric Repeat Binding Protein 2 / genetics
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Telomeric Repeat Binding Protein 2 / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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ATG5 protein, human
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Autophagy-Related Protein 5
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Cell Cycle Proteins
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DNA-Binding Proteins
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Diamines
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H2AX protein, human
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Histones
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Ligands
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Luminescent Proteins
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MAP1LC3A protein, human
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Microtubule-Associated Proteins
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N'-(10H-indolo(3,2-b)quinolin-11-yl)-N,N-dimethylpropane-1,3-diamine
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Quinolines
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Telomeric Repeat Binding Protein 2
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Tumor Suppressor Proteins
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases