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

Tumor necrosis factor alpha (TNF alpha) 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 TNF alpha stimulation by altering signaling cross-talks. Thus, varying the extent of signaling cross-talk could enable optimal TNF alpha 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 TNF alpha receptor and NF kappa B, 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. Author summary TNF alpha mediated apoptosis, a form of cell-death, is the desired outcome for cancer therapeutics. This outcome is governed by complex regulation involving several signaling entities stimulated by TNF alpha. Relating the transient levels of these entities over early phase of the signaling response to the late-phase cell-death is a challenge. We developed a knowledge and data-driven mathematical model to unravel the dynamic synergistic correlation between the early transients governing the apoptotic response. Using flux balance and branch analysis, we demonstrated that the dynamic cross-talk between different key signaling entities regulates the apoptotic response. We performed inhibitory experiments predicted by model simulations and thereby established that cells tweak the extent of synergism during signal transduction to modulate the apoptotic response in a time-dependent manner. Thus, our approach provides useful insights for identifying signaling targets to arrive at novel combinatorial cancer therapies.