Model-based identification of the crosstalks and feedbacks that determine the doxorubicin response dynamics of the JNK-p38-p53 network

Abstract

Cellular responses to perturbations and drugs are determined by interconnected networks, rather than linear pathways. Individually, the JNK, p38 and p53 stress and DNA-damage response networks are well understood and regulate critical cell-fate decisions, such as apoptosis, in response to many chemotherapeutical agents, such as doxorubicin. To better understand how interactions between these pathways determine the dynamic behaviour of the entire network, we constructed a data-driven mathematical model. This model contains mechanistic details about the kinase cascades that activate JNK, p38, AKT and p53, and free parameters that describe possible interactions between these pathways. Fitting this model to experimental time-course perturbation data (five time-courses with six time-points under five different conditions), identified specific network interactions that can explain the observed network responses. JNK emerged as an important control node. JNK exhibited a positive feedback loop, was tightly controlled by negative feedback and crosstalk from p38 and AKT, respectively, and was the strongest activator of p53. Compared to static network reconstruction methods, such as modular response analysis, the model-based approach identifies biochemical mechanisms and explains the dynamic control of cell signalling.

Doxorubicin-Induced TrkAIII Activation: A Selection Mechanism for Resistant Dormant Neuroblastoma Cells

“…This suggests that this mechanism results from Dox-induced, TrkAIII-mediated, IP3-K/Akt-dependent prosurvival signaling. This is consistent with previous reports that TrkAIII induces pro-survival IP3-K/Akt signaling [27,28] and that Akt mediates Dox resistance in NB cells [18][19][20][21][22][23]. The induction of unconventional Xbp-1 splicing by Dox negates the inhibition of the Ire1a/XBP1 arm of the UPR in this resistance mechanism [63], while PP1 did not prevent Dox-induced TrkAIII activation, indicating that any potential Src involvement would be downstream of TrkAIII [24].…”

“…Akt exerts its pro-survival effects through multiple mechanisms, including the inhibition of Fas ligand expression, the induction of BAD phosphorylation leading to Bcl-xL release, the inhibition of pro-apoptotic caspase-9, glycogen synthase kinase 3-β [18], and the ZAK/MKKK4/MKKK7/JNK module [20,22]. In addition, Dox-resistant NB cells secrete factors that activate pro-survival STAT3 and Akt signaling in neighboring Dox-sensitive cells [18,22,23]. NB cells also exhibit dox-induced pro-survival Src signaling in association with an impaired p53 function [24].…”