The tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis
in malignant cells, while leaving other cells mostly unharmed. However, several
carcinomas remain resistant to TRAIL. To investigate the resistance mechanisms in
TRAIL-stimulated human fibrosarcoma (HT1080) cells, we developed a computational
model to analyze the temporal activation profiles of cell survival (IκB, JNK, p38)
and apoptotic (caspase-8 and -3) molecules in wildtype and several (FADD, RIP1,
TRAF2 and caspase-8) knock-down conditions. Based on perturbation-response approach
utilizing the law of information (signaling flux) conservation, we derived response
rules for population-level average cell response. From this approach, i) a
FADD-independent pathway to activate p38 and JNK, ii) a crosstalk between RIP1 and
p38, and iii) a crosstalk between p62 and JNK are predicted. Notably, subsequent
simulations suggest that targeting a novel molecule at p62/sequestosome-1 junction
will optimize apoptosis through signaling flux redistribution. This study
offers a valuable prospective to sensitive TRAIL-based therapy.