CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells

Despite the potential apoptotic functions, the CD95/CD95L system can stimulate survival as well as pro-inflammatory signaling, particularly through the activation of NFκB. This holds true for the TNF/TNFR and the TRAIL/TRAILR systems. Thus, signaling pathways of these three death ligands converge, y...

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Autores principales:	Khalid Rashid, Christian Röder, Freya Goumas, Jan-Hendrik Egberts, Holger Kalthoff
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	gemcitabine death ligands chemoresistance PDAC metastasis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/ad66080d7cec487dbc933b75115dda68
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spelling	oai:doaj.org-article:ad66080d7cec487dbc933b75115dda682021-11-11T15:33:30ZCD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells10.3390/cancers132154582072-6694https://doaj.org/article/ad66080d7cec487dbc933b75115dda682021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5458https://doaj.org/toc/2072-6694Despite the potential apoptotic functions, the CD95/CD95L system can stimulate survival as well as pro-inflammatory signaling, particularly through the activation of NFκB. This holds true for the TNF/TNFR and the TRAIL/TRAILR systems. Thus, signaling pathways of these three death ligands converge, yet the specific impact of the CD95/CD95L system in this crosstalk has not been well studied. In this study, we show that gemcitabine stimulates the expression of pro-inflammatory cytokines, such as IL6 and IL8, under the influence of the CD95/CD95L system and the pharmacological inhibitor, sCD95Fc, substantially reduced the expression in two PDAC cell lines, PancTuI-luc and A818-4. The stem cell phenotype was reduced when induced upon gemcitabine as well by sCD95Fc. Moreover, TNF-α as well as TRAIL up-regulate the expression of CD95 and CD95L in both cell lines. Conversely, we detected a significant inhibitory effect of sCD95Fc on the expression of both IL8 and IL6 induced upon TNF-α and TRAIL stimulation. In vivo, CD95L inhibition reduced xeno-transplanted recurrent PDAC growth. Thus, our findings indicate that inhibition of CD95 signaling altered the chemotherapeutic effects of gemcitabine, not only by suppressing the pro-inflammatory responses that arose from the CD95L-positive tumor cells but also from the TNF-α and TRAIL signaling in a bi-lateral crosstalk manner.Khalid RashidChristian RöderFreya GoumasJan-Hendrik EgbertsHolger KalthoffMDPI AGarticlegemcitabinedeath ligandschemoresistancePDACmetastasisNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5458, p 5458 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	gemcitabine death ligands chemoresistance PDAC metastasis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	gemcitabine death ligands chemoresistance PDAC metastasis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Khalid Rashid Christian Röder Freya Goumas Jan-Hendrik Egberts Holger Kalthoff CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells
description	Despite the potential apoptotic functions, the CD95/CD95L system can stimulate survival as well as pro-inflammatory signaling, particularly through the activation of NFκB. This holds true for the TNF/TNFR and the TRAIL/TRAILR systems. Thus, signaling pathways of these three death ligands converge, yet the specific impact of the CD95/CD95L system in this crosstalk has not been well studied. In this study, we show that gemcitabine stimulates the expression of pro-inflammatory cytokines, such as IL6 and IL8, under the influence of the CD95/CD95L system and the pharmacological inhibitor, sCD95Fc, substantially reduced the expression in two PDAC cell lines, PancTuI-luc and A818-4. The stem cell phenotype was reduced when induced upon gemcitabine as well by sCD95Fc. Moreover, TNF-α as well as TRAIL up-regulate the expression of CD95 and CD95L in both cell lines. Conversely, we detected a significant inhibitory effect of sCD95Fc on the expression of both IL8 and IL6 induced upon TNF-α and TRAIL stimulation. In vivo, CD95L inhibition reduced xeno-transplanted recurrent PDAC growth. Thus, our findings indicate that inhibition of CD95 signaling altered the chemotherapeutic effects of gemcitabine, not only by suppressing the pro-inflammatory responses that arose from the CD95L-positive tumor cells but also from the TNF-α and TRAIL signaling in a bi-lateral crosstalk manner.
format	article
author	Khalid Rashid Christian Röder Freya Goumas Jan-Hendrik Egberts Holger Kalthoff
author_facet	Khalid Rashid Christian Röder Freya Goumas Jan-Hendrik Egberts Holger Kalthoff
author_sort	Khalid Rashid
title	CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells
title_short	CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells
title_full	CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells
title_fullStr	CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells
title_full_unstemmed	CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells
title_sort	cd95l inhibition impacts gemcitabine-mediated effects and non-apoptotic signaling of tnf-α and trail in pancreatic tumor cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ad66080d7cec487dbc933b75115dda68
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CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells

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