Article ; Online: Interplay of p53 and XIAP protein dynamics orchestrates cell fate in response to chemotherapy.
Journal of theoretical biology
2023 Volume 572, Page(s) 111562
Abstract: Chemotherapeutic drugs are used to treat almost all types of cancer, but the intended response, i.e., elimination, is often incomplete, with a subset of cancer cells resisting treatment. Two critical factors play a role in chemoresistance: the p53 tumour ...
| Abstract | Chemotherapeutic drugs are used to treat almost all types of cancer, but the intended response, i.e., elimination, is often incomplete, with a subset of cancer cells resisting treatment. Two critical factors play a role in chemoresistance: the p53 tumour suppressor gene and the X-linked inhibitor of apoptosis (XIAP). These proteins have been shown to act synergistically to elicit cellular responses upon DNA damage induced by chemotherapy, yet, the mechanism is poorly understood. This study introduces a mathematical model characterising the apoptosis pathway activation by p53 before and after mitochondrial outer membrane permeabilisation upon treatment with the chemotherapy Doxorubicin (Dox). "In-silico" simulations show that the p53 dynamics change dose-dependently. Under medium to high doses of Dox, p53 concentration ultimately stabilises to a high level regardless of XIAP concentrations. However, caspase-3 activation may be triggered or not depending on the XIAP induction rate, ultimately determining whether the cell will perish or resist. Consequently, the model predicts that failure to activate apoptosis in some cancer cells expressing wild-type p53 might be due to heterogeneity between cells in upregulating the XIAP protein, rather than due to the p53 protein concentration. Our model suggests that the interplay of the p53 dynamics and the XIAP induction rate is critical to determine the cancer cells' therapeutic response. |
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| MeSH term(s) | X-Linked Inhibitor of Apoptosis Protein/genetics ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; Tumor Suppressor Protein p53/metabolism ; Apoptosis/physiology ; Cell Death ; Doxorubicin/pharmacology ; Cell Line, Tumor |
| Chemical Substances | X-Linked Inhibitor of Apoptosis Protein ; Tumor Suppressor Protein p53 ; Doxorubicin (80168379AG) |
| Language | English |
| Publishing date | 2023-06-20 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2972-5 |
| ISSN | 1095-8541 ; 0022-5193 |
| ISSN (online) | 1095-8541 |
| ISSN | 0022-5193 |
| DOI | 10.1016/j.jtbi.2023.111562 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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