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Abstract
Death ligand mediated apoptotic activation is a mode of programmed cell death that is widely used in cellular and physiological situations. Interest in studying death ligand induced apoptosis has increased due to the promising role of recombinant soluble forms of death ligands (mainly recombinant TRAIL) in anti-cancer therapy. A clear elucidation of how death ligands activate the type 1 and type 2 apoptotic pathways in healthy and cancer cells may help develop better chemotherapeutic strategies. In this work, we use kinetic Monte Carlo simulations to address the problem of type 1/ type 2 choice in death ligand mediated apoptosis of cancer cells. Our study provides insights into the activation of membrane proximal death module that results from complex interplay between death and decoy receptors. Relative abundance of death and decoy receptors was shown to be a key parameter for activation of the initiator caspases in the membrane module. Increased concentration of death ligands frequently increased the type 1 activation fraction in cancer cells, and, in certain cases changes the signaling phenotype from type 2 to type 1. Results of this study also indicate that inherent differences between cancer and healthy cells, such as in the membrane module, may allow robust activation of cancer cell apoptosis by death ligand induction. At the same time, large cell-to-cell variability through the type 2 pathway was shown to provide protection for healthy cells. Such elucidation of selective activation of apoptosis in cancer cells addresses a key question in cancer biology and cancer therapy.
Highlights
Death ligand induced apoptosis is a frequently used mode of cell death activation and is important for its potential application in cancer therapy
We study the effect of variation in death ligands on apoptotic activation in such representative cancer cells
Type 2 to type 1 transition seems to allow a stochastic-to-deterministic change in apoptotic activation. In certain cancers, such a stochastic-to-deterministic change will be possible to achieve by combinatorial treatments, such as by the combined action of Tumor necrosis factor related apoptosis inducing ligand (TRAIL) and XIAP inhibitors [3] [14] [18]
Summary
Death ligand induced apoptosis is a frequently used mode of cell death activation and is important for its potential application in cancer therapy. Death ligands are known to engage their specific receptors (death receptors) and can activate type 1 and type 2 apoptotic pathways. A clear mechanistic understanding of such selectivity in TRAIL induced apoptosis in cancer cells is still lacking. Expression levels of various pro- and anti-apoptotic molecules in the membrane proximal and other signaling modules (in the apoptotic pathway) may modulate selectivity in cancer cell apoptosis. In a more general manner, the systems level regulatory mechanisms (such as the type 1/ type 2 choice) of death ligand induced activation of the apoptotic death pathway need to be clearly elucidated. Presence of decoy receptors that are capable of engaging the death ligands makes it difficult to understand the mechanisms of death ligand induced activation of the membrane proximal module. Two distinct clustering mechanisms have been indicated for TRAIL decoy receptors [2] [5] providing additional complexities into the problem
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