cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells

Abstract Deficiencies in DNA repair and DNA degrading nucleases lead to accumulation of cytosolic DNA. cGAS is a critical DNA sensor for the detection of cytosolic DNA and subsequent activation of the STING signaling pathway. Here, we show that the cGAS-STING pathway was unresponsive to STING agonis...

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Autores principales:	Manuel Adrian Suter, Nikki Y. Tan, Chung Hwee Thiam, Muznah Khatoo, Paul A. MacAry, Veronique Angeli, Stephan Gasser, Y. L. Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/79ec77f2ebf949149c0b66f12a1493ef
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spelling	oai:doaj.org-article:79ec77f2ebf949149c0b66f12a1493ef2021-12-02T14:24:56ZcGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells10.1038/s41598-021-86644-x2045-2322https://doaj.org/article/79ec77f2ebf949149c0b66f12a1493ef2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86644-xhttps://doaj.org/toc/2045-2322Abstract Deficiencies in DNA repair and DNA degrading nucleases lead to accumulation of cytosolic DNA. cGAS is a critical DNA sensor for the detection of cytosolic DNA and subsequent activation of the STING signaling pathway. Here, we show that the cGAS-STING pathway was unresponsive to STING agonists and failed to induce type I interferon (IFN) expression in many tested human tumor cells including DU145 prostate cancer cells. Inhibition of IL-6 or the downstream JAK2/STAT3 signaling restored responsiveness to STING agonists in DU145 cells. STING activity in murine TRAMP-C2 prostate cancer cells was critical for tumor rejection and immune cell infiltration. Endogenous STING agonists including double-stranded DNA and RNA:DNA hybrids present in TRAMP-C2 cells contribute to tumor rejection, but tumor growth was further suppressed by administration of cGAMP. Intratumoral co-injections of IL-6 significantly reduced the anti-tumor effects of cGAMP. In summary, STING in tumor cells contributes to tumor rejection in prostate cancer cells, but its functions are frequently suppressed in tumor cells in part via JAK2 and STAT3 pathways.Manuel Adrian SuterNikki Y. TanChung Hwee ThiamMuznah KhatooPaul A. MacAryVeronique AngeliStephan GasserY. L. ZhangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Manuel Adrian Suter Nikki Y. Tan Chung Hwee Thiam Muznah Khatoo Paul A. MacAry Veronique Angeli Stephan Gasser Y. L. Zhang cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells
description	Abstract Deficiencies in DNA repair and DNA degrading nucleases lead to accumulation of cytosolic DNA. cGAS is a critical DNA sensor for the detection of cytosolic DNA and subsequent activation of the STING signaling pathway. Here, we show that the cGAS-STING pathway was unresponsive to STING agonists and failed to induce type I interferon (IFN) expression in many tested human tumor cells including DU145 prostate cancer cells. Inhibition of IL-6 or the downstream JAK2/STAT3 signaling restored responsiveness to STING agonists in DU145 cells. STING activity in murine TRAMP-C2 prostate cancer cells was critical for tumor rejection and immune cell infiltration. Endogenous STING agonists including double-stranded DNA and RNA:DNA hybrids present in TRAMP-C2 cells contribute to tumor rejection, but tumor growth was further suppressed by administration of cGAMP. Intratumoral co-injections of IL-6 significantly reduced the anti-tumor effects of cGAMP. In summary, STING in tumor cells contributes to tumor rejection in prostate cancer cells, but its functions are frequently suppressed in tumor cells in part via JAK2 and STAT3 pathways.
format	article
author	Manuel Adrian Suter Nikki Y. Tan Chung Hwee Thiam Muznah Khatoo Paul A. MacAry Veronique Angeli Stephan Gasser Y. L. Zhang
author_facet	Manuel Adrian Suter Nikki Y. Tan Chung Hwee Thiam Muznah Khatoo Paul A. MacAry Veronique Angeli Stephan Gasser Y. L. Zhang
author_sort	Manuel Adrian Suter
title	cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells
title_short	cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells
title_full	cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells
title_fullStr	cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells
title_full_unstemmed	cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells
title_sort	cgas–sting cytosolic dna sensing pathway is suppressed by jak2-stat3 in tumor cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/79ec77f2ebf949149c0b66f12a1493ef
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cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells

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