Raghavendra A. Shamanna
Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer
Shamanna, Raghavendra A.; Lu, Huiming; Croteau, Deborah L.; Arora, Arvind; Agarwal, Devika; Ball, Graham; Aleskandarany, Mohammed A.; Ellis, Ian O.; Pommier, Yves; Madhusudan, Srinivasan; Bohr, Vilhelm A.
Authors
Huiming Lu
Deborah L. Croteau
Arvind Arora
Devika Agarwal
Graham Ball
Mohammed A. Aleskandarany
Professor IAN ELLIS IAN.ELLIS@NOTTINGHAM.AC.UK
Professor of Cancer Pathology
Yves Pommier
SRINIVASAN MADHUSUDAN srinivasan.madhusudan@nottingham.ac.uk
Professor of Medical Oncology
Vilhelm A. Bohr
Abstract
Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated ?-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens.
Citation
Shamanna, R. A., Lu, H., Croteau, D. L., Arora, A., Agarwal, D., Ball, G., …Bohr, V. A. (2016). Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer. Oncotarget, 7(12), 13269-13284. https://doi.org/10.18632/oncotarget.7906
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 9, 2016 |
Online Publication Date | Mar 3, 2016 |
Publication Date | Mar 22, 2016 |
Deposit Date | Aug 8, 2019 |
Publicly Available Date | Aug 8, 2019 |
Journal | Oncotarget |
Electronic ISSN | 1949-2553 |
Publisher | Impact Journals |
Peer Reviewed | Peer Reviewed |
Volume | 7 |
Issue | 12 |
Pages | 13269-13284 |
DOI | https://doi.org/10.18632/oncotarget.7906 |
Public URL | https://nottingham-repository.worktribe.com/output/2408448 |
Publisher URL | http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=7906&path[]=23137 |
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Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer
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Publisher Licence URL
https://creativecommons.org/licenses/by/3.0/
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