title: 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.
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0035, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa, 252-8520, Japan.
authors.forename: Vincent
authors.initials: V
authors.lastname: Piras
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Masaru
authors.initials: M
authors.lastname: Tomita
authors.forename: Kumar
authors.initials: K
authors.lastname: Selvarajoo
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
chemical_list: C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D020169:Caspases