Enhancing apoptosis in TRAIL-resistant cancer cells using fundamental response rules

Vincent Piras, Kentaro Hayashi, Masaru Tomita, Kumar Selvarajoo

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 (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.

Original languageEnglish
Article number144
JournalScientific reports
Volume1
DOIs
Publication statusPublished - 2011 Dec 1

ASJC Scopus subject areas

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