2024-03-28T21:05:50Z
https://tsukuba.repo.nii.ac.jp/oai
oai:tsukuba.repo.nii.ac.jp:00041503
2022-04-27T09:12:25Z
160:1251
3:62:5298:5045
Withaferin-A kills cancer cells with and without telomerase: chemical, computational and experimental evidences
張, 振亜
Yu, Yue
Katiyar, Shashank P
Sundar, Durai
Kaul, Zeenia
Miyako, Eijiro
Zhang, Zhenya
Kaul, Sunil C
Reddel, Roger R
Wadhwa, Renu
Maintenance of telomere length is the most consistent attribute of cancer cells. Tightly connected to their capacity to overcome replicative mortality, it is achieved either by activation of telomerase or an Alternative mechanism of Lengthening of Telomeres (ALT). Disruption of either of these mechanisms has been shown to induce DNA damage signalling leading to senescence or apoptosis. Telomerase inhibitors are considered as potential anticancer drugs but are ineffective for ALT cancers (~15% of all cancers). Withaferin-A (Wi-A), a major constituent of the medicinal plant, Withania somnifera (Ashwagandha), has been shown to exert anti-tumour activity. However, its effect on either telomerase or ALT mechanisms has not been investigated. Here, by using isogenic cancer cells with/without telomerase, we found that Wi-A caused stronger cytotoxicity to ALT cells. It was associated with inhibition of ALT-associated promyelocytic leukemia nuclear bodies, an established marker of ALT. Comparative analyses of telomerase positive and ALT cells revealed that Wi-A caused stronger telomere dysfunction and upregulation of DNA damage response in ALT cells. Molecular computational and experimental analyses revealed that Wi-A led to Myc-Mad mediated transcriptional suppression of NBS-1, an MRN complex protein that is an essential component of the ALT mechanism. The results suggest that Wi-A could be a new candidate drug for ALT cancers.
journal article
Nature Publishing Group
2017-04
application/pdf
Cell Death and Disease
8
e2755
2041-4889
https://tsukuba.repo.nii.ac.jp/record/41503/files/CD&D_2017-8.pdf
eng
28425984
10.1038/cddis.2017.33
© The Author(s) 2017
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.