Unraveling the intracellular cross-talk governing the balance between TNFα mediated survival and apoptosis signaling

Abstract

Tumor necrosis factor alpha (TNF), a pleiotropic cytokine, helps maintain a balance between proliferation and apoptosis in normal cells. This balance is often sacrificed in a diseased cell, such as that of a cancer, by preferring survival phenotype over apoptosis. Restoring this balance requires a detailed understanding of the causal intracellular mechanisms that govern TNF stimulated apoptotic response. In this study, we use a systems biology approach to unravel the interplay between the intracellular signaling markers that orchestrate apoptosis levels. Our approach deciphered the synergism between the early intracellular markers phosphorylated JNK (pJNK) and phosphorylated AKT (pAKT) that modulate the activation of Caspase3, an important apoptotic regulator. We demonstrate that this synergism depends critically on the survival pathway signaling mediated by NF{kappa}B which plays a dominant role in controlling the extent of the overall apoptotic response. By systematic inhibition of the signaling markers, we establish that the dynamic cross-talk between the pJNK and pAKT transients directs the apoptosis phenotype via accumulated Caspase3 response. Interestingly, superposition of the semi-quantitative correlation between apoptosis and Caspase3 transient levels on the proposed TNF network model permits quantification of the dynamic apoptotic response under different stimulation conditions. Thus, the predictive model can be leveraged towards arriving at useful insights that can identify potential targeted therapeutic strategies for altering apoptotic response.