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FInal Published Version
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Univ Arizona, Dept Mol & Cellular BiolIssue Date
2017-08-14
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NATURE PUBLISHING GROUPCitation
A dynamical framework for complex fractional killing 2017, 7 (1) Scientific ReportsJournal
Scientific ReportsRights
© The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
When chemotherapy drugs are applied to tumor cells with the same or similar genotypes, some cells are killed, while others survive. This fractional killing contributes to drug resistance in cancer. Through an incoherent feedforward loop, chemotherapy drugs not only activate p53 to induce cell death, but also promote the expression of apoptosis inhibitors which inhibit cell death. Consequently, cells in which p53 is activated early undergo apoptosis while cells in which p53 is activated late survive. The incoherent feedforward loop and the essential role of p53 activation timing makes fractional killing a complex dynamical challenge, which is hard to understand with intuition alone. To better understand this process, we have constructed a representative model by integrating the control of apoptosis with the relevant signaling pathways. After the model was trained to recapture the observed properties of fractional killing, it was analyzed with nonlinear dynamical tools. The analysis suggested a simple dynamical framework for fractional killing, which predicts that cell fate can be altered in three possible ways: alteration of bifurcation geometry, alteration of cell trajectories, or both. These predicted categories can explain existing strategies known to combat fractional killing and facilitate the design of novel strategies.ISSN
2045-2322Version
Final published versionAdditional Links
http://www.nature.com/articles/s41598-017-07422-2ae974a485f413a2113503eed53cd6c53
10.1038/s41598-017-07422-2