TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3

Aims: Preferential expression of receptors for TNF-family related apoptosis inducing ligand (TRAIL), DR4 and DR5 makes TRAIL an attractive anti-cancer therapeutic. However, the efficacy of targeting death receptors has not been extensively studied in nasopharyngeal cancer (NPC). Here we investigated...

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Autores principales:	Deepika Raman, Patricia Tay, Jayshree L. Hirpara, Dan Liu, Shazib Pervaiz
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	NPC TRAIL Peroxynitrite Caspase-3 TMTC2 Medicine (General) R5-920 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c988189fef44465cb005a770bf3e81f5
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spelling	oai:doaj.org-article:c988189fef44465cb005a770bf3e81f52021-11-28T04:31:23ZTRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-32213-231710.1016/j.redox.2021.102193https://doaj.org/article/c988189fef44465cb005a770bf3e81f52021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2213231721003530https://doaj.org/toc/2213-2317Aims: Preferential expression of receptors for TNF-family related apoptosis inducing ligand (TRAIL), DR4 and DR5 makes TRAIL an attractive anti-cancer therapeutic. However, the efficacy of targeting death receptors has not been extensively studied in nasopharyngeal cancer (NPC). Here we investigated TRAIL sensitivity and its underlying mechanism in NPC cell lines, and assessed the potential of TRAIL as a therapeutic option against NPC. Results: Using two established NPC cell lines, we report the expression of DR4 and DR5, which respond to TRAIL ligation by triggering efficient Type II apoptosis. Mechanistically, early activation of caspase-3 and its membrane recruitment is identified in NPC cell lines, which is associated with, hitherto unreported, interaction with transmembrane and tetratricopeptide repeat containing 2 (TMTC2) in the lipid raft domains. TMTC2 expression is induced upon exposure to TRAIL and involves intracellular increase in peroxynitrite (ONOO−) production. While ONOO− increase is downstream of caspase-8 activation, it is involved in the upregulation of TMTC2, gene knockdown of which abrogated TRAIL-induced apoptotic execution. Bioinformatics analyses also provide evidence for a strong correlation between TMTC2 and DR4 or caspase-3 as well as a significantly better disease-free survival in patients with high TMTC2 expression. Innovation and conclusion: Collectively, redox-dependent execution of NPC cells upon ligation of TRAIL receptors reintroduces the possible therapeutic use of TRAIL in NPC as well as underscores the potential of using TMTC2 as a biomarker of TRAIL sensitivity.Deepika RamanPatricia TayJayshree L. HirparaDan LiuShazib PervaizElsevierarticleNPCTRAILPeroxynitriteCaspase-3TMTC2Medicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102193- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NPC TRAIL Peroxynitrite Caspase-3 TMTC2 Medicine (General) R5-920 Biology (General) QH301-705.5
spellingShingle	NPC TRAIL Peroxynitrite Caspase-3 TMTC2 Medicine (General) R5-920 Biology (General) QH301-705.5 Deepika Raman Patricia Tay Jayshree L. Hirpara Dan Liu Shazib Pervaiz TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3
description	Aims: Preferential expression of receptors for TNF-family related apoptosis inducing ligand (TRAIL), DR4 and DR5 makes TRAIL an attractive anti-cancer therapeutic. However, the efficacy of targeting death receptors has not been extensively studied in nasopharyngeal cancer (NPC). Here we investigated TRAIL sensitivity and its underlying mechanism in NPC cell lines, and assessed the potential of TRAIL as a therapeutic option against NPC. Results: Using two established NPC cell lines, we report the expression of DR4 and DR5, which respond to TRAIL ligation by triggering efficient Type II apoptosis. Mechanistically, early activation of caspase-3 and its membrane recruitment is identified in NPC cell lines, which is associated with, hitherto unreported, interaction with transmembrane and tetratricopeptide repeat containing 2 (TMTC2) in the lipid raft domains. TMTC2 expression is induced upon exposure to TRAIL and involves intracellular increase in peroxynitrite (ONOO−) production. While ONOO− increase is downstream of caspase-8 activation, it is involved in the upregulation of TMTC2, gene knockdown of which abrogated TRAIL-induced apoptotic execution. Bioinformatics analyses also provide evidence for a strong correlation between TMTC2 and DR4 or caspase-3 as well as a significantly better disease-free survival in patients with high TMTC2 expression. Innovation and conclusion: Collectively, redox-dependent execution of NPC cells upon ligation of TRAIL receptors reintroduces the possible therapeutic use of TRAIL in NPC as well as underscores the potential of using TMTC2 as a biomarker of TRAIL sensitivity.
format	article
author	Deepika Raman Patricia Tay Jayshree L. Hirpara Dan Liu Shazib Pervaiz
author_facet	Deepika Raman Patricia Tay Jayshree L. Hirpara Dan Liu Shazib Pervaiz
author_sort	Deepika Raman
title	TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3
title_short	TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3
title_full	TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3
title_fullStr	TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3
title_full_unstemmed	TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3
title_sort	trail sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of tmtc2 and its interaction with membrane caspase-3
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/c988189fef44465cb005a770bf3e81f5
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TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3

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