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RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer

Cancer-derived small extracellular vesicles (sEVs) serve as critical mediators of cell-to-cell communication. Manzamine A (MA), a unique marine-derived alkaloid with various bioactivities, exerts anticancer effects against several kinds of tumors, but it remains unclear whether it has the same activ...

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Autores principales: Wang, Xuan, Liu, Yuanpeng, Qin, Huan, Qi, Guocui, Chen, Xuehong, Lyu, Yi, Han, Yantao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051755/
https://www.ncbi.nlm.nih.gov/pubmed/36976201
http://dx.doi.org/10.3390/md21030151
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author Wang, Xuan
Liu, Yuanpeng
Qin, Huan
Qi, Guocui
Chen, Xuehong
Lyu, Yi
Han, Yantao
author_facet Wang, Xuan
Liu, Yuanpeng
Qin, Huan
Qi, Guocui
Chen, Xuehong
Lyu, Yi
Han, Yantao
author_sort Wang, Xuan
collection PubMed
description Cancer-derived small extracellular vesicles (sEVs) serve as critical mediators of cell-to-cell communication. Manzamine A (MA), a unique marine-derived alkaloid with various bioactivities, exerts anticancer effects against several kinds of tumors, but it remains unclear whether it has the same activity against breast cancer. Here, we proved that MA inhibits MDA-MB-231 and MCF-7 cell proliferation, migration, and invasion in a time- and dose-dependent manner. In addition, MA promotes autophagosome formation but suppresses autophagosome degradation in breast cancer cells. Importantly, we also found that MA stimulates sEVs secretion and increases autophagy-related protein accumulation in secreted sEVs, further potentiated by autophagy inhibitor chloroquine (CQ). Mechanistically, MA decreases the expression level of RIP1, the key upstream regulator of the autophagic pathway, and reduces the acidity of lysosome. Overexpression of RIP1 activated AKT/mTOR signaling, thus attenuating MA-induced autophagy and the corresponding secretion of autophagy-associated sEVs. Collectively, these data suggested that MA is a potential inhibitor of autophagy by preventing autophagosome turnover, and RIP1 mediates MA-induced secretory autophagy, which may be efficacious for breast cancer treatment.
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spelling pubmed-100517552023-03-30 RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer Wang, Xuan Liu, Yuanpeng Qin, Huan Qi, Guocui Chen, Xuehong Lyu, Yi Han, Yantao Mar Drugs Article Cancer-derived small extracellular vesicles (sEVs) serve as critical mediators of cell-to-cell communication. Manzamine A (MA), a unique marine-derived alkaloid with various bioactivities, exerts anticancer effects against several kinds of tumors, but it remains unclear whether it has the same activity against breast cancer. Here, we proved that MA inhibits MDA-MB-231 and MCF-7 cell proliferation, migration, and invasion in a time- and dose-dependent manner. In addition, MA promotes autophagosome formation but suppresses autophagosome degradation in breast cancer cells. Importantly, we also found that MA stimulates sEVs secretion and increases autophagy-related protein accumulation in secreted sEVs, further potentiated by autophagy inhibitor chloroquine (CQ). Mechanistically, MA decreases the expression level of RIP1, the key upstream regulator of the autophagic pathway, and reduces the acidity of lysosome. Overexpression of RIP1 activated AKT/mTOR signaling, thus attenuating MA-induced autophagy and the corresponding secretion of autophagy-associated sEVs. Collectively, these data suggested that MA is a potential inhibitor of autophagy by preventing autophagosome turnover, and RIP1 mediates MA-induced secretory autophagy, which may be efficacious for breast cancer treatment. MDPI 2023-02-25 /pmc/articles/PMC10051755/ /pubmed/36976201 http://dx.doi.org/10.3390/md21030151 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Xuan
Liu, Yuanpeng
Qin, Huan
Qi, Guocui
Chen, Xuehong
Lyu, Yi
Han, Yantao
RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer
title RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer
title_full RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer
title_fullStr RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer
title_full_unstemmed RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer
title_short RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer
title_sort rip1 mediates manzamine-a-induced secretory autophagy in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051755/
https://www.ncbi.nlm.nih.gov/pubmed/36976201
http://dx.doi.org/10.3390/md21030151
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