Replogle, J. M., Zhou, W., Amaro, A. E., McFarland, J. M., Villalobos-Ortiz, M., Ryan, J., Letai, A., Yilmaz, O., Sheltzer, J., Lippard, S. J., Ben-David, U., Amon, A.
(December 2020)
Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division.
Proc Natl Acad Sci U S A, 117 (48).
pp. 30566-30576.
ISSN 0027-8424 (Print)0027-8424
Abstract
Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition-G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.
| Item Type: |
Paper
|
| Additional Information: |
1091-6490
Replogle, John Michael
Zhou, Wen
Orcid: 0000-0001-8455-6011
Amaro, Adrianna E
McFarland, James M
Villalobos-Ortiz, Mariana
Ryan, Jeremy
Orcid: 0000-0002-3327-1283
Letai, Anthony
Yilmaz, Omer
Sheltzer, Jason
Lippard, Stephen J
Ben-David, Uri
Amon, Angelika
HHMI/Howard Hughes Medical Institute/United States
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30566-30576. doi: 10.1073/pnas.2009506117. Epub 2020 Nov 17. |
| Uncontrolled Keywords: |
*aneuploidy
*cell cycle
*chemotherapy resistance
*cisplatin
*paclitaxel
have not collaborated directly on this project. |
| Subjects: |
bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomal duplications > aneuploidy
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomal duplications
organs, tissues, organelles, cell types and functions |
| CSHL Authors: |
|
| Communities: |
CSHL labs > Sheltzer lab |
| Depositing User: |
Matthew Dunn
|
| Date: |
1 December 2020 |
| Date Deposited: |
19 Feb 2021 19:48 |
| Last Modified: |
01 Feb 2024 17:01 |
| PMCID: |
PMC7720170 |
| Related URLs: |
|
| URI: |
https://repository.cshl.edu/id/eprint/39877 |
Actions (login required)
 |
Administrator's edit/view item |
