Enhancing apoptosis in TRAIL-resistant cancer cells using fundamental response rules
- PMID: 22355661
- PMCID: PMC3216625
- DOI: 10.1038/srep00144
Enhancing apoptosis in TRAIL-resistant cancer cells using fundamental response rules
Abstract
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.
Figures
between simulations and
experimental data for the ith molecule in the
kth condition is calculated based on the area
between experimental and simulation curves (see Eq. 5 in Methods).
*caspase-8 KD also refers to pro-caspase-8 KD.
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