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Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer

Overview of attention for article published in Oncotarget, March 2016
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Title
Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer
Published in
Oncotarget, March 2016
DOI 10.18632/oncotarget.7906
Pubmed ID
Authors

Raghavendra A. Shamanna, Huiming Lu, Deborah L. Croteau, Arvind Arora, Devika Agarwal, Graham Ball, Mohammed A. Aleskandarany, Ian O. Ellis, Yves Pommier, Srinivasan Madhusudan, 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 β-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.

Mendeley readers

The data shown below were compiled from readership statistics for 61 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 1 2%
Unknown 60 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 14 23%
Researcher 12 20%
Student > Master 7 11%
Student > Bachelor 7 11%
Student > Doctoral Student 3 5%
Other 12 20%
Unknown 6 10%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 26 43%
Agricultural and Biological Sciences 13 21%
Medicine and Dentistry 8 13%
Chemistry 4 7%
Immunology and Microbiology 2 3%
Other 2 3%
Unknown 6 10%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 March 2018.
All research outputs
#11,251,246
of 12,639,455 outputs
Outputs from Oncotarget
#7,952
of 11,837 outputs
Outputs of similar age
#236,499
of 271,979 outputs
Outputs of similar age from Oncotarget
#274
of 414 outputs
Altmetric has tracked 12,639,455 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 11,837 research outputs from this source. They receive a mean Attention Score of 3.7. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 271,979 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 414 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.