TY - JOUR
T1 - Enhancing apoptosis in TRAIL-resistant cancer cells using fundamental response rules
AU - Piras, Vincent
AU - Hayashi, Kentaro
AU - Tomita, Masaru
AU - Selvarajoo, Kumar
N1 - Funding Information:
We thank Daiki Yamada and Masa Tsuchiya for initial collaboration and Tomoe Egashita (Takara Biosciences) for experimental support. This work was supported by the research fund of Yamagata Prefecture and Tsuruoka City, Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research F11815, and Japan Student Services Organization (JASSO).
PY - 2011
Y1 - 2011
N2 - 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 (IkB, 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.
AB - 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 (IkB, 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.
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U2 - 10.1038/srep00144
DO - 10.1038/srep00144
M3 - Article
C2 - 22355661
AN - SCOPUS:84859746988
SN - 2045-2322
VL - 1
JO - Scientific reports
JF - Scientific reports
M1 - 144
ER -
