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

Scientific Reports
Vincent PirasKumar Selvarajoo

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.

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Citations

Oct 1, 2013·Trends in Molecular Medicine·Daniel W Stuckey, Khalid Shah
Nov 10, 2013·Cell Communication and Signaling : CCS·Kentaro HayashiKumar Selvarajoo
May 31, 2014·Cell Death & Disease·I N Lavrik
May 16, 2012·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Kumar Selvarajoo
Aug 25, 2015·Frontiers in Genetics·Kumar Selvarajoo
Jul 23, 2013·International Immunopharmacology·Liuqin YangDianchun Fang
Jan 21, 2015·Frontiers in Immunology·Kentaro HayashiKumar Selvarajoo
Apr 8, 2017·Scientific Reports·Mei-Chuan ChenShiow-Lin Pan
Aug 8, 2020·International Journal of Molecular Sciences·Manikandan MuthuJae-Wook Oh
Feb 23, 2019·NPJ Systems Biology and Applications·William DeveauxKumar Selvarajoo

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Software Mentioned

ImageJ
TRAIL

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