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Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death

G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Che...

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Autores principales: Liu, Rui, Liu, Jing, Wang, Shuqing, Wang, Yinsong, Zhang, Tao, liu, Yang, Geng, Xin, Wang, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624283/
https://www.ncbi.nlm.nih.gov/pubmed/31296842
http://dx.doi.org/10.1038/s41419-019-1768-x
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author Liu, Rui
Liu, Jing
Wang, Shuqing
Wang, Yinsong
Zhang, Tao
liu, Yang
Geng, Xin
Wang, Feng
author_facet Liu, Rui
Liu, Jing
Wang, Shuqing
Wang, Yinsong
Zhang, Tao
liu, Yang
Geng, Xin
Wang, Feng
author_sort Liu, Rui
collection PubMed
description G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation.
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spelling pubmed-66242832019-07-15 Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death Liu, Rui Liu, Jing Wang, Shuqing Wang, Yinsong Zhang, Tao liu, Yang Geng, Xin Wang, Feng Cell Death Dis Article G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation. Nature Publishing Group UK 2019-07-11 /pmc/articles/PMC6624283/ /pubmed/31296842 http://dx.doi.org/10.1038/s41419-019-1768-x Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Liu, Rui
Liu, Jing
Wang, Shuqing
Wang, Yinsong
Zhang, Tao
liu, Yang
Geng, Xin
Wang, Feng
Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
title Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
title_full Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
title_fullStr Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
title_full_unstemmed Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
title_short Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
title_sort combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624283/
https://www.ncbi.nlm.nih.gov/pubmed/31296842
http://dx.doi.org/10.1038/s41419-019-1768-x
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