The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways

Prostate cancer (PCa) is a leading cause of cancer-related deaths among men worldwide, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides represent an attractive group of candidates for anticancer repurposing, but the cardiac glycoside deslanoside has not been tested for po...

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Autores principales:	Mingcheng Liu, Qingqing Huang, Jun A, Linyue Li, Xiawei Li, Zhiqian Zhang, Jin-Tang Dong
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	prostate cancer deslanoside anticancer therapy cardiac glycosides Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/bf6d3160c54142aa9b99ffae61e23119
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spelling	oai:doaj.org-article:bf6d3160c54142aa9b99ffae61e231192021-11-25T17:04:16ZThe Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways10.3390/cancers132258092072-6694https://doaj.org/article/bf6d3160c54142aa9b99ffae61e231192021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5809https://doaj.org/toc/2072-6694Prostate cancer (PCa) is a leading cause of cancer-related deaths among men worldwide, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides represent an attractive group of candidates for anticancer repurposing, but the cardiac glycoside deslanoside has not been tested for potential anticancer activity so far. We found that deslanoside effectively inhibited colony formation in vitro and tumor growth in nude mice of PCa cell lines 22Rv1, PC-3, and DU 145. Such an anticancer activity was mediated by both the cell cycle arrest at G2/M and the induction of apoptosis, as demonstrated by different functional assays and the expression status of regulatory proteins of cell cycle and apoptosis in cultured cells. Moreover, deslanoside suppressed the invasion and migration of PCa cell lines. Genome-wide expression profiling and bioinformatic analyses revealed that 130 genes were either upregulated or downregulated by deslanoside in both 22Rv1 and PC-3 cell lines. These genes enriched multiple cellular processes, such as response to steroid hormones, regulation of lipid metabolism, epithelial cell proliferation and its regulation, and negative regulation of cell migration. They also enriched multiple signaling pathways, such as necroptosis, MAPK, NOD-like receptor, and focal adhesion. Survival analyses of the 130 genes in the TCGA PCa database revealed that 10 of the deslanoside-downregulated genes (<i>ITG2B</i>, <i>CNIH2</i>, <i>FBF1</i>, <i>PABPC1L</i>, <i>MMP11</i>, <i>DUSP9</i>, <i>TMEM121</i>, <i>SOX18</i>, <i>CMPK2</i>, and <i>MAMDC4</i>) inversely correlated, while one deslanoside-upregulated gene (<i>RASD1</i>) positively correlated, with disease-free survival in PCa patients. In addition, one deslanoside-downregulated gene (<i>ENG</i>) inversely correlated, while three upregulated genes (<i>JUN</i>, <i>MXD1</i>, and <i>AQP3</i>) positively correlated with overall survival in PCa patients. Some of the 15 genes have not been implicated in cancer before. These findings provide another candidate for repurposing cardiac glycosides for anticancer drugs. They also suggest that a diverse range of molecular events underlie deslanoside’s anticancer activity in PCa cells.Mingcheng LiuQingqing HuangJun ALinyue LiXiawei LiZhiqian ZhangJin-Tang DongMDPI AGarticleprostate cancerdeslanosideanticancer therapycardiac glycosidesNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5809, p 5809 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	prostate cancer deslanoside anticancer therapy cardiac glycosides Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	prostate cancer deslanoside anticancer therapy cardiac glycosides Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mingcheng Liu Qingqing Huang Jun A Linyue Li Xiawei Li Zhiqian Zhang Jin-Tang Dong The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways
description	Prostate cancer (PCa) is a leading cause of cancer-related deaths among men worldwide, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides represent an attractive group of candidates for anticancer repurposing, but the cardiac glycoside deslanoside has not been tested for potential anticancer activity so far. We found that deslanoside effectively inhibited colony formation in vitro and tumor growth in nude mice of PCa cell lines 22Rv1, PC-3, and DU 145. Such an anticancer activity was mediated by both the cell cycle arrest at G2/M and the induction of apoptosis, as demonstrated by different functional assays and the expression status of regulatory proteins of cell cycle and apoptosis in cultured cells. Moreover, deslanoside suppressed the invasion and migration of PCa cell lines. Genome-wide expression profiling and bioinformatic analyses revealed that 130 genes were either upregulated or downregulated by deslanoside in both 22Rv1 and PC-3 cell lines. These genes enriched multiple cellular processes, such as response to steroid hormones, regulation of lipid metabolism, epithelial cell proliferation and its regulation, and negative regulation of cell migration. They also enriched multiple signaling pathways, such as necroptosis, MAPK, NOD-like receptor, and focal adhesion. Survival analyses of the 130 genes in the TCGA PCa database revealed that 10 of the deslanoside-downregulated genes (<i>ITG2B</i>, <i>CNIH2</i>, <i>FBF1</i>, <i>PABPC1L</i>, <i>MMP11</i>, <i>DUSP9</i>, <i>TMEM121</i>, <i>SOX18</i>, <i>CMPK2</i>, and <i>MAMDC4</i>) inversely correlated, while one deslanoside-upregulated gene (<i>RASD1</i>) positively correlated, with disease-free survival in PCa patients. In addition, one deslanoside-downregulated gene (<i>ENG</i>) inversely correlated, while three upregulated genes (<i>JUN</i>, <i>MXD1</i>, and <i>AQP3</i>) positively correlated with overall survival in PCa patients. Some of the 15 genes have not been implicated in cancer before. These findings provide another candidate for repurposing cardiac glycosides for anticancer drugs. They also suggest that a diverse range of molecular events underlie deslanoside’s anticancer activity in PCa cells.
format	article
author	Mingcheng Liu Qingqing Huang Jun A Linyue Li Xiawei Li Zhiqian Zhang Jin-Tang Dong
author_facet	Mingcheng Liu Qingqing Huang Jun A Linyue Li Xiawei Li Zhiqian Zhang Jin-Tang Dong
author_sort	Mingcheng Liu
title	The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways
title_short	The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways
title_full	The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways
title_fullStr	The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways
title_full_unstemmed	The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways
title_sort	cardiac glycoside deslanoside exerts anticancer activity in prostate cancer cells by modulating multiple signaling pathways
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bf6d3160c54142aa9b99ffae61e23119
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The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways

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