  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.
