Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell death in various types of cancer cells but has little or no effects on normal cells. Unfortunately, not all cancer cells respond to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. Here, we reported...

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Autores principales:	Tingting Lin, Yong Chen, Zhiying Ding, Guimin Luo, Junqiu Liu, Jiacong Shen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fd97bb9a6d7643318916bbb0e2b0bbc5
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spelling	oai:doaj.org-article:fd97bb9a6d7643318916bbb0e2b0bbc52021-11-18T07:45:27ZNovel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.1932-620310.1371/journal.pone.0063966https://doaj.org/article/fd97bb9a6d7643318916bbb0e2b0bbc52013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23696862/?tool=EBIhttps://doaj.org/toc/1932-6203Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell death in various types of cancer cells but has little or no effects on normal cells. Unfortunately, not all cancer cells respond to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. Here, we reported that 6-(4-N,N-dimethylaminophenyltelluro)-6-deoxy-β-cyclodextrin (DTCD), a cyclodextrin-derived diorganyl telluride which has been identified as an excellent inhibitor of thioredoxin reductase (TrxR), could sensitize TRAIL resistant human ovarian cancer cells to undergo apoptosis. In vitro, DTCD enhanced TRAIL-induced cytotoxicity in human ovarian cancer cells through up-regulation of DR5. Luciferase analysis and CHIP assays showed that DTCD increased DR5 promoter activity via Sp1 activation. Additionally, DTCD stimulated extracellular signal-regulated kinase (ERK) activation, while the ERK inhibitor PD98059 blocked DTCD-induced DR5 expression and suppressed binding of Sp1 to the DR5 promoter. We further demonstrated that DTCD could induce the release of ASK1 from its complex with Trx-1, and recovered its kinase activity. Meanwhile, suppression of ASK1 by RNA interference led to decreased ERK phosphorylation induced by DTCD. The underlying mechanisms reveal that Trx-1 is heavily oxidized in response to DTCD treatment, in accordance with the fact that DTCD could inhibit the activity of TrxR that reduces oxidized Trx-1. Moreover, using an A2780 xenograft model, DTCD plus TRAIL significantly inhibited the growth of tumor in vivo. Our results suggest that Trx/TrxR system inhibition may play a critical role in apoptosis by combined treatment with DTCD and TRAIL, and raise the possibility that their combination may be a promising strategy for ovarian carcinoma treatment.Tingting LinYong ChenZhiying DingGuimin LuoJunqiu LiuJiacong ShenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e63966 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tingting Lin Yong Chen Zhiying Ding Guimin Luo Junqiu Liu Jiacong Shen Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.
description	Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell death in various types of cancer cells but has little or no effects on normal cells. Unfortunately, not all cancer cells respond to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. Here, we reported that 6-(4-N,N-dimethylaminophenyltelluro)-6-deoxy-β-cyclodextrin (DTCD), a cyclodextrin-derived diorganyl telluride which has been identified as an excellent inhibitor of thioredoxin reductase (TrxR), could sensitize TRAIL resistant human ovarian cancer cells to undergo apoptosis. In vitro, DTCD enhanced TRAIL-induced cytotoxicity in human ovarian cancer cells through up-regulation of DR5. Luciferase analysis and CHIP assays showed that DTCD increased DR5 promoter activity via Sp1 activation. Additionally, DTCD stimulated extracellular signal-regulated kinase (ERK) activation, while the ERK inhibitor PD98059 blocked DTCD-induced DR5 expression and suppressed binding of Sp1 to the DR5 promoter. We further demonstrated that DTCD could induce the release of ASK1 from its complex with Trx-1, and recovered its kinase activity. Meanwhile, suppression of ASK1 by RNA interference led to decreased ERK phosphorylation induced by DTCD. The underlying mechanisms reveal that Trx-1 is heavily oxidized in response to DTCD treatment, in accordance with the fact that DTCD could inhibit the activity of TrxR that reduces oxidized Trx-1. Moreover, using an A2780 xenograft model, DTCD plus TRAIL significantly inhibited the growth of tumor in vivo. Our results suggest that Trx/TrxR system inhibition may play a critical role in apoptosis by combined treatment with DTCD and TRAIL, and raise the possibility that their combination may be a promising strategy for ovarian carcinoma treatment.
format	article
author	Tingting Lin Yong Chen Zhiying Ding Guimin Luo Junqiu Liu Jiacong Shen
author_facet	Tingting Lin Yong Chen Zhiying Ding Guimin Luo Junqiu Liu Jiacong Shen
author_sort	Tingting Lin
title	Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.
title_short	Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.
title_full	Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.
title_fullStr	Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.
title_full_unstemmed	Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.
title_sort	novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and trail: the activation of the ask1-erk-sp1 pathway.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/fd97bb9a6d7643318916bbb0e2b0bbc5
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Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway.

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