Interplay of p53 and XIAP protein dynamics orchestrates cell fate in response to chemotherapy

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). \textit{``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.

P53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect

“…Another study has introduced a two-phase dynamic of p53, distinguishing between partial and complete activation of p53 (Zhang et al, 2011). Our recent study expanded on these findings by demonstrating that p53 can switch among three dynamic modes in a DNA damage strength-dependent manner following chemotherapy (Abukwaik et al, 2023). Despite these advances, earlier works have mainly concentrated on p53 dynamic behaviour in response to DNA damage stimuli and the subsequent cell fate, leaving a substantial gap in understanding its mechanisms regarding cellular metabolism.…”