A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways

Abstract Triple-negative breast cancer (TNBC) is a high-risk subtype of breast cancer with high capacity for metastasis and lacking of therapeutic targets. Our previous studies indicated that cystathionine γ-lyase (CSE) may be a new target related to the recurrence or metastasis of TNBC. Downregulat...

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Autores principales:	Ya Liu, Lupeng Wang, Xiuli Zhang, Yuying Deng, Limin Pan, Hui Li, Xiaoyan Shi, Tianxiao Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6ee730420102402986db3c8ac9a8330d
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spelling	oai:doaj.org-article:6ee730420102402986db3c8ac9a8330d2021-12-02T13:41:00ZA novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways10.1038/s41598-021-88355-92045-2322https://doaj.org/article/6ee730420102402986db3c8ac9a8330d2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88355-9https://doaj.org/toc/2045-2322Abstract Triple-negative breast cancer (TNBC) is a high-risk subtype of breast cancer with high capacity for metastasis and lacking of therapeutic targets. Our previous studies indicated that cystathionine γ-lyase (CSE) may be a new target related to the recurrence or metastasis of TNBC. Downregulation of CSE could inhibit the growth and metastasis of TNBC. The purpose of this study was to investigate the activity of the novel CSE inhibitor I194496 against TNBC in vivo and in vitro. The anticancer activity of I194496 in vitro were detected by MTS, EdU, and transwell assays. Methylene blue assay was used to determine the H2S level. Western blot was performed to analyze the expression of related pathway proteins. Xenograft tumors in nude mice were used to analyze the anticancer activity of I194496 in vivo. I194496 exerted potent inhibitory effects than l-propargylglycine (PAG, an existing CSE inhibitor) on human TNBC cells and possessed lower toxicity in normal breast epithelial Hs578Bst cells. I194496 reduced the activity and expression of CSE protein and the release of H2S in human TNBC cells. Meanwhile, the protein levels of PI3K, Akt, phospho (p)-Akt, Ras, Raf, p-ERK, p-Anxa2, STAT3, p-STAT3, VEGF, FAK, and Paxillin were decreased in human TNBC cells administrated with I194496. Furthermore, I194496 showed more stronger inhibitory effects on human TNBC xenograft tumors in nude mice. I194496 could inhibit the growth of human TNBC cells via the dual targeting PI3K/Akt and Ras/Raf/ERK pathway and suppress the metastasis of human TNBC cells via down-regulating Anxa2/STAT3 and VEGF/FAK/Paxillin signaling pathways. CSE inhibitor I194496 might become a novel and potential agent in the treatment of TNBC.Ya LiuLupeng WangXiuli ZhangYuying DengLimin PanHui LiXiaoyan ShiTianxiao WangNature 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 Ya Liu Lupeng Wang Xiuli Zhang Yuying Deng Limin Pan Hui Li Xiaoyan Shi Tianxiao Wang A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways
description	Abstract Triple-negative breast cancer (TNBC) is a high-risk subtype of breast cancer with high capacity for metastasis and lacking of therapeutic targets. Our previous studies indicated that cystathionine γ-lyase (CSE) may be a new target related to the recurrence or metastasis of TNBC. Downregulation of CSE could inhibit the growth and metastasis of TNBC. The purpose of this study was to investigate the activity of the novel CSE inhibitor I194496 against TNBC in vivo and in vitro. The anticancer activity of I194496 in vitro were detected by MTS, EdU, and transwell assays. Methylene blue assay was used to determine the H2S level. Western blot was performed to analyze the expression of related pathway proteins. Xenograft tumors in nude mice were used to analyze the anticancer activity of I194496 in vivo. I194496 exerted potent inhibitory effects than l-propargylglycine (PAG, an existing CSE inhibitor) on human TNBC cells and possessed lower toxicity in normal breast epithelial Hs578Bst cells. I194496 reduced the activity and expression of CSE protein and the release of H2S in human TNBC cells. Meanwhile, the protein levels of PI3K, Akt, phospho (p)-Akt, Ras, Raf, p-ERK, p-Anxa2, STAT3, p-STAT3, VEGF, FAK, and Paxillin were decreased in human TNBC cells administrated with I194496. Furthermore, I194496 showed more stronger inhibitory effects on human TNBC xenograft tumors in nude mice. I194496 could inhibit the growth of human TNBC cells via the dual targeting PI3K/Akt and Ras/Raf/ERK pathway and suppress the metastasis of human TNBC cells via down-regulating Anxa2/STAT3 and VEGF/FAK/Paxillin signaling pathways. CSE inhibitor I194496 might become a novel and potential agent in the treatment of TNBC.
format	article
author	Ya Liu Lupeng Wang Xiuli Zhang Yuying Deng Limin Pan Hui Li Xiaoyan Shi Tianxiao Wang
author_facet	Ya Liu Lupeng Wang Xiuli Zhang Yuying Deng Limin Pan Hui Li Xiaoyan Shi Tianxiao Wang
author_sort	Ya Liu
title	A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways
title_short	A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways
title_full	A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways
title_fullStr	A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways
title_full_unstemmed	A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways
title_sort	novel cystathionine γ-lyase inhibitor, i194496, inhibits the growth and metastasis of human tnbc via downregulating multiple signaling pathways
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6ee730420102402986db3c8ac9a8330d
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A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways

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