RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis

Abstract The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer. In TNBC, Aquaporin 1 (AQP1), a water-transporting transmembrane protein, is aberrantly enriched in cytoplasm and causes tumor cell death evasion. However, the carcinogenetic bioactivities of cytopla...

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Autores principales:	Zhuming Yin, Wenlin Chen, Jian Yin, Jingyan Sun, Qianrong Xie, Min Wu, Fanxin Zeng, Huiwen Ren
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f09adfa3bbe341e7862bef9fb05ee956
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spelling	oai:doaj.org-article:f09adfa3bbe341e7862bef9fb05ee9562021-12-02T15:42:38ZRIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis10.1038/s41523-021-00261-52374-4677https://doaj.org/article/f09adfa3bbe341e7862bef9fb05ee9562021-05-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00261-5https://doaj.org/toc/2374-4677Abstract The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer. In TNBC, Aquaporin 1 (AQP1), a water-transporting transmembrane protein, is aberrantly enriched in cytoplasm and causes tumor cell death evasion. However, the carcinogenetic bioactivities of cytoplasmic AQP1 cannot be attributed to the canonical “osmotic engine model”. In the present study, the receptor-interacting protein kinase 1 (RIPK1), a cell death regulator, was identified to negatively mediate AQP1-driven TNBC progression and metastasis. AQP1 overabundance and RIPK1 depletion occurred in TNBC, which were correlated with aggressive oncological features and poor prognosis. AQP1 bound with RIPK1, resulting in the inhibition of RIPK1/RIPK3/MLKL-mediated necroptosis and RIPK1/caspase-8/caspase-3-mediated apoptosis. Genetic inhibition of RIPK1 significantly exacerbated the pro-tumor effect of AQP1, while ectopic expression of RIPK1 notably blunted AQP1 signaling. Mechanistically, AQP1 binds to the D324 site of RIPK1, and facilitates RIPK1 cleavage and inactivation by excessively activating the caspase-8/RIPK1 negative feedback loop. RIPK1D324K overexpression significantly prevented RIPK1 cleavage and weakened the aggressiveness of AQP1-enriched TNBC cells. Overall, our findings clarify the underlying mechanism of cytoplasmic AQP1-driven TNBC progression and metastasis, in which RIPK1 exerts an essential role as a negative mediator and exhibits the potential as a therapeutic target for TNBC.Zhuming YinWenlin ChenJian YinJingyan SunQianrong XieMin WuFanxin ZengHuiwen RenNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Zhuming Yin Wenlin Chen Jian Yin Jingyan Sun Qianrong Xie Min Wu Fanxin Zeng Huiwen Ren RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis
description	Abstract The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer. In TNBC, Aquaporin 1 (AQP1), a water-transporting transmembrane protein, is aberrantly enriched in cytoplasm and causes tumor cell death evasion. However, the carcinogenetic bioactivities of cytoplasmic AQP1 cannot be attributed to the canonical “osmotic engine model”. In the present study, the receptor-interacting protein kinase 1 (RIPK1), a cell death regulator, was identified to negatively mediate AQP1-driven TNBC progression and metastasis. AQP1 overabundance and RIPK1 depletion occurred in TNBC, which were correlated with aggressive oncological features and poor prognosis. AQP1 bound with RIPK1, resulting in the inhibition of RIPK1/RIPK3/MLKL-mediated necroptosis and RIPK1/caspase-8/caspase-3-mediated apoptosis. Genetic inhibition of RIPK1 significantly exacerbated the pro-tumor effect of AQP1, while ectopic expression of RIPK1 notably blunted AQP1 signaling. Mechanistically, AQP1 binds to the D324 site of RIPK1, and facilitates RIPK1 cleavage and inactivation by excessively activating the caspase-8/RIPK1 negative feedback loop. RIPK1D324K overexpression significantly prevented RIPK1 cleavage and weakened the aggressiveness of AQP1-enriched TNBC cells. Overall, our findings clarify the underlying mechanism of cytoplasmic AQP1-driven TNBC progression and metastasis, in which RIPK1 exerts an essential role as a negative mediator and exhibits the potential as a therapeutic target for TNBC.
format	article
author	Zhuming Yin Wenlin Chen Jian Yin Jingyan Sun Qianrong Xie Min Wu Fanxin Zeng Huiwen Ren
author_facet	Zhuming Yin Wenlin Chen Jian Yin Jingyan Sun Qianrong Xie Min Wu Fanxin Zeng Huiwen Ren
author_sort	Zhuming Yin
title	RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis
title_short	RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis
title_full	RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis
title_fullStr	RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis
title_full_unstemmed	RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis
title_sort	ripk1 is a negative mediator in aquaporin 1-driven triple-negative breast carcinoma progression and metastasis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f09adfa3bbe341e7862bef9fb05ee956
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RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis

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