Modulation of signaling cross-talk between pJNK and pAKT generates optimal apoptotic response

Abstract

Tumor necrosis factor alpha (TNFα) is a well-known modulator of apoptosis by maintaining a balance between proliferation and cell-death in normal cells. Cancer cells often evade apoptotic response following TNFα stimulation by altering signaling cross-talks. Thus, varying the extent of signaling cross-talk could enable optimal TNFα mediated apoptotic dynamics. Herein, we use an experimental data-driven mathematical modeling to quantitate the extent of synergistic signaling cross-talk between the intracellular entities phosphorylated JNK (pJNK) and phosphorylated AKT (pAKT) that orchestrate the phenotypic apoptosis level by modulating the activated Caspase3 dynamics. Our study reveals that this modulation is orchestrated by the distinct dynamic nature of the synergism at early and late phases. We show that this synergism in signal flow is governed by branches originating from either TNFα receptor and NFκB, which facilitates signaling through survival pathways. We demonstrate that the experimentally quantified apoptosis levels semi-quantitatively correlates with the model simulated Caspase3 transients. Interestingly, perturbing pJNK and pAKT transient dynamics fine-tunes this accumulated Caspase3 guided apoptotic response. Thus, our study offers useful insights for identifying potential targeted therapies for optimal apoptotic response.