Systems Biology Strategy Reveals PKC-delta is Key for Sensitizing TRAIL-Resistant Human Fibrosarcoma

Cancer cells are highly variable and resistant to therapeutic intervention. Recently, the use of the tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced treatment is gaining momentum, due to TRAIL’s ability to specifically target cancers with limited effect on normal cells. Howev...

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Main Authors: Kentaro eHayashi, Sho eTabata, Vincent ePiras, Masaru eTomita, Kumar eSelvarajoo
Format: Article
Language:English
Published: Frontiers Media S.A. 2015-01-01
Series:Frontiers in Immunology
Subjects:
Online Access:http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00659/full
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spelling doaj-0dca174bf9da49a3a999e7816ade13f82020-11-25T00:23:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242015-01-01510.3389/fimmu.2014.00659107305Systems Biology Strategy Reveals PKC-delta is Key for Sensitizing TRAIL-Resistant Human FibrosarcomaKentaro eHayashi0Kentaro eHayashi1Sho eTabata2Sho eTabata3Vincent ePiras4Vincent ePiras5Masaru eTomita6Masaru eTomita7Kumar eSelvarajoo8Kumar eSelvarajoo9Keio UniversityKeio UniversityKeio UniversityKeio UniversityKeio UniversityKeio UniversityKeio UniversityKeio UniversityKeio UniversityKeio UniversityCancer cells are highly variable and resistant to therapeutic intervention. Recently, the use of the tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced treatment is gaining momentum, due to TRAIL’s ability to specifically target cancers with limited effect on normal cells. However, several malignant cancer types still remain non-sensitive to TRAIL. Previously, we developed a dynamic computational model, based on perturbation-response approach, and predicted protein kinase C (PKC) as the most effective target, with over 95% capacity to kill human fibrosarcoma (HT1080) in TRAIL stimulation (Piras, V. et al. 2011, Scientific Reports). Here, to validate the model prediction, which has significant implications for cancer treatment, we conducted experiments on two TRAIL-resistant cancer cell lines (HT1080 and HT29). Using PKC inhibitor Bisindolylmaleimide I, we first demonstrate, as predicted by our previous model, cell viability is significantly impaired with over 95% death of both cancer types. Next, to identify crucial PKC isoform from 10 known members, we analyzed their mRNA expressions in HT1080 cells and shortlisted 4 isoforms for siRNA knock-down (KD) experiments. From these KDs, PKC-delta produced the most cancer cell death in conjunction with TRAIL. Overall, systems biology approach, combining model prediction with experimental validation, holds promise for TRAIL-based cancer therapy.http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00659/fullApoptosisProtein Kinase CCancercomputational modelingcell dynamicsSignaling Pathways
collection DOAJ
language English
format Article
sources DOAJ
author Kentaro eHayashi
Kentaro eHayashi
Sho eTabata
Sho eTabata
Vincent ePiras
Vincent ePiras
Masaru eTomita
Masaru eTomita
Kumar eSelvarajoo
Kumar eSelvarajoo
spellingShingle Kentaro eHayashi
Kentaro eHayashi
Sho eTabata
Sho eTabata
Vincent ePiras
Vincent ePiras
Masaru eTomita
Masaru eTomita
Kumar eSelvarajoo
Kumar eSelvarajoo
Systems Biology Strategy Reveals PKC-delta is Key for Sensitizing TRAIL-Resistant Human Fibrosarcoma
Frontiers in Immunology
Apoptosis
Protein Kinase C
Cancer
computational modeling
cell dynamics
Signaling Pathways
author_facet Kentaro eHayashi
Kentaro eHayashi
Sho eTabata
Sho eTabata
Vincent ePiras
Vincent ePiras
Masaru eTomita
Masaru eTomita
Kumar eSelvarajoo
Kumar eSelvarajoo
author_sort Kentaro eHayashi
title Systems Biology Strategy Reveals PKC-delta is Key for Sensitizing TRAIL-Resistant Human Fibrosarcoma
title_short Systems Biology Strategy Reveals PKC-delta is Key for Sensitizing TRAIL-Resistant Human Fibrosarcoma
title_full Systems Biology Strategy Reveals PKC-delta is Key for Sensitizing TRAIL-Resistant Human Fibrosarcoma
title_fullStr Systems Biology Strategy Reveals PKC-delta is Key for Sensitizing TRAIL-Resistant Human Fibrosarcoma
title_full_unstemmed Systems Biology Strategy Reveals PKC-delta is Key for Sensitizing TRAIL-Resistant Human Fibrosarcoma
title_sort systems biology strategy reveals pkc-delta is key for sensitizing trail-resistant human fibrosarcoma
publisher Frontiers Media S.A.
series Frontiers in Immunology
issn 1664-3224
publishDate 2015-01-01
description Cancer cells are highly variable and resistant to therapeutic intervention. Recently, the use of the tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced treatment is gaining momentum, due to TRAIL’s ability to specifically target cancers with limited effect on normal cells. However, several malignant cancer types still remain non-sensitive to TRAIL. Previously, we developed a dynamic computational model, based on perturbation-response approach, and predicted protein kinase C (PKC) as the most effective target, with over 95% capacity to kill human fibrosarcoma (HT1080) in TRAIL stimulation (Piras, V. et al. 2011, Scientific Reports). Here, to validate the model prediction, which has significant implications for cancer treatment, we conducted experiments on two TRAIL-resistant cancer cell lines (HT1080 and HT29). Using PKC inhibitor Bisindolylmaleimide I, we first demonstrate, as predicted by our previous model, cell viability is significantly impaired with over 95% death of both cancer types. Next, to identify crucial PKC isoform from 10 known members, we analyzed their mRNA expressions in HT1080 cells and shortlisted 4 isoforms for siRNA knock-down (KD) experiments. From these KDs, PKC-delta produced the most cancer cell death in conjunction with TRAIL. Overall, systems biology approach, combining model prediction with experimental validation, holds promise for TRAIL-based cancer therapy.
topic Apoptosis
Protein Kinase C
Cancer
computational modeling
cell dynamics
Signaling Pathways
url http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00659/full
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