Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation

Chronic psychological stress is closely correlated with breast cancer growth and metastasis. Sini San (SNS) formula is a classical prescription for relieving depression-related symptoms in traditional Chinese medicine (TCM). Current researches have suggested that chronic psychological stress is clos...

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Autores principales:	Yifeng Zheng, Juping Zhang, Wanqing Huang, Linda L. D. Zhong, Neng Wang, Shengqi Wang, Bowen Yang, Xuan Wang, Bo Pan, Honglin Situ, Yi Lin, Xiaoyan Liu, Yafei Shi, Zhiyu Wang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Sini San breast cancer stem cells chronic psychological stress GRP78/LRP5 cortisol Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/5ef94a3f0dfc4389b747891bfd972332
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spelling	oai:doaj.org-article:5ef94a3f0dfc4389b747891bfd9723322021-12-01T14:03:03ZSini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation1663-981210.3389/fphar.2021.714163https://doaj.org/article/5ef94a3f0dfc4389b747891bfd9723322021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.714163/fullhttps://doaj.org/toc/1663-9812Chronic psychological stress is closely correlated with breast cancer growth and metastasis. Sini San (SNS) formula is a classical prescription for relieving depression-related symptoms in traditional Chinese medicine (TCM). Current researches have suggested that chronic psychological stress is closely correlated with cancer stem cells (CSCs) and endoplasmic reticulum (ER) stress. This study aimed to investigate the effects of chronic psychological stress on ER stress-mediated breast cancer stemness and the therapeutic implication of SNS. Chronic psychological stress promoted lung metastasis in 4T1 breast tumor-bearing mice and increased the stem cell-like populations and stemness-related gene expression. Meanwhile, GRP78, a marker of ER stress, was significantly increased in the breast tumors and lung metastases under chronic psychological stress. As a biochemical hallmark of chronic psychological stress, cortisol dramatically enhanced the stem cell-like populations and mammospheres formation by activating GRP78 transcriptionally. However, GRP78 inhibitors or shRNA attenuated the stemness enhancement mediated by cortisol. Similarly, SNS inhibited chronic psychological stress-induced lung metastasis and stemness of breast cancer cells, as well as reversed cortisol-induced stem cell-like populations and mammospheres formation by attenuating GRP78 expression. Co-localization and co-immunoprecipitation experiments showed that SNS interrupted the interaction between GRP78 and LRP5 on the cell surface, thus inhibiting the Wnt/β-catenin signaling of breast CSCs. Altogether, this study not only uncovers the biological influence and molecular mechanism of chronic psychological stress on breast CSCs but also highlights SNS as a promising strategy for relieving GRP78-induced breast cancer stemness via inhibiting GRP78 activation.Yifeng ZhengYifeng ZhengYifeng ZhengJuping ZhangWanqing HuangLinda L. D. ZhongLinda L. D. ZhongNeng WangNeng WangNeng WangShengqi WangShengqi WangShengqi WangBowen YangXuan WangBo PanHonglin SituYi LinXiaoyan LiuYafei ShiZhiyu WangZhiyu WangZhiyu WangZhiyu WangZhiyu WangFrontiers Media S.A.articleSini Sanbreast cancer stem cellschronic psychological stressGRP78/LRP5cortisolTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Sini San breast cancer stem cells chronic psychological stress GRP78/LRP5 cortisol Therapeutics. Pharmacology RM1-950
spellingShingle	Sini San breast cancer stem cells chronic psychological stress GRP78/LRP5 cortisol Therapeutics. Pharmacology RM1-950 Yifeng Zheng Yifeng Zheng Yifeng Zheng Juping Zhang Wanqing Huang Linda L. D. Zhong Linda L. D. Zhong Neng Wang Neng Wang Neng Wang Shengqi Wang Shengqi Wang Shengqi Wang Bowen Yang Xuan Wang Bo Pan Honglin Situ Yi Lin Xiaoyan Liu Yafei Shi Zhiyu Wang Zhiyu Wang Zhiyu Wang Zhiyu Wang Zhiyu Wang Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation
description	Chronic psychological stress is closely correlated with breast cancer growth and metastasis. Sini San (SNS) formula is a classical prescription for relieving depression-related symptoms in traditional Chinese medicine (TCM). Current researches have suggested that chronic psychological stress is closely correlated with cancer stem cells (CSCs) and endoplasmic reticulum (ER) stress. This study aimed to investigate the effects of chronic psychological stress on ER stress-mediated breast cancer stemness and the therapeutic implication of SNS. Chronic psychological stress promoted lung metastasis in 4T1 breast tumor-bearing mice and increased the stem cell-like populations and stemness-related gene expression. Meanwhile, GRP78, a marker of ER stress, was significantly increased in the breast tumors and lung metastases under chronic psychological stress. As a biochemical hallmark of chronic psychological stress, cortisol dramatically enhanced the stem cell-like populations and mammospheres formation by activating GRP78 transcriptionally. However, GRP78 inhibitors or shRNA attenuated the stemness enhancement mediated by cortisol. Similarly, SNS inhibited chronic psychological stress-induced lung metastasis and stemness of breast cancer cells, as well as reversed cortisol-induced stem cell-like populations and mammospheres formation by attenuating GRP78 expression. Co-localization and co-immunoprecipitation experiments showed that SNS interrupted the interaction between GRP78 and LRP5 on the cell surface, thus inhibiting the Wnt/β-catenin signaling of breast CSCs. Altogether, this study not only uncovers the biological influence and molecular mechanism of chronic psychological stress on breast CSCs but also highlights SNS as a promising strategy for relieving GRP78-induced breast cancer stemness via inhibiting GRP78 activation.
format	article
author	Yifeng Zheng Yifeng Zheng Yifeng Zheng Juping Zhang Wanqing Huang Linda L. D. Zhong Linda L. D. Zhong Neng Wang Neng Wang Neng Wang Shengqi Wang Shengqi Wang Shengqi Wang Bowen Yang Xuan Wang Bo Pan Honglin Situ Yi Lin Xiaoyan Liu Yafei Shi Zhiyu Wang Zhiyu Wang Zhiyu Wang Zhiyu Wang Zhiyu Wang
author_facet	Yifeng Zheng Yifeng Zheng Yifeng Zheng Juping Zhang Wanqing Huang Linda L. D. Zhong Linda L. D. Zhong Neng Wang Neng Wang Neng Wang Shengqi Wang Shengqi Wang Shengqi Wang Bowen Yang Xuan Wang Bo Pan Honglin Situ Yi Lin Xiaoyan Liu Yafei Shi Zhiyu Wang Zhiyu Wang Zhiyu Wang Zhiyu Wang Zhiyu Wang
author_sort	Yifeng Zheng
title	Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation
title_short	Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation
title_full	Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation
title_fullStr	Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation
title_full_unstemmed	Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation
title_sort	sini san inhibits chronic psychological stress-induced breast cancer stemness by suppressing cortisol-mediated grp78 activation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/5ef94a3f0dfc4389b747891bfd972332
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Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation

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