Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer

Drug resistance has become one of the largest challenges for cancer chemotherapies. Under certain conditions, cancer cells hijack autophagy to cope with therapeutic stress, which largely undermines the chemo-therapeutic efficacy. Currently, biomarkers indicative of autophagy-derived drug resistance...

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Autores principales:	Yin Shi, Zu Ye, Guang Lu, Naidi Yang, Jianbin Zhang, Liming Wang, Jianzhou Cui, Miguel A. del Pozo, Yihua Wu, Dajing Xia, Han-Ming Shen
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	autophagy breast cancer doxorubicin resistance cholesterol-enriched membrane micro-domains CAV1 VAMP3 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/784d7619203943aa977f70f75746777f
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spelling	oai:doaj.org-article:784d7619203943aa977f70f75746777f2021-11-04T04:33:01ZCholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer2372-770510.1016/j.omto.2021.10.005https://doaj.org/article/784d7619203943aa977f70f75746777f2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S237277052100142Xhttps://doaj.org/toc/2372-7705Drug resistance has become one of the largest challenges for cancer chemotherapies. Under certain conditions, cancer cells hijack autophagy to cope with therapeutic stress, which largely undermines the chemo-therapeutic efficacy. Currently, biomarkers indicative of autophagy-derived drug resistance remain largely inclusive. Here, we report a novel role of lipid rafts/cholesterol-enriched membrane micro-domains (CEMMs) in autophagosome biogenesis and doxorubicin resistance in breast tumors. We showed that CEMMs are required for the interaction of VAMP3 with syntaxin 6 (STX6, a cholesterol-binding SNARE protein). Upon disruption of CEMM, VAMP3 is released from STX6, resulting in the trafficking of ATG16L1-containing vesicles to recycling endosomes and subsequent autophagosome biogenesis. Furthermore, we found that CEMM marker CAV1 is decreased in breast cancer patients and that the CEMM deficiency-induced autophagy is related to doxorubicin resistance, which is overcome by autophagy inhibition. Taken together, we propose a novel model whereby CEMMs in recycling endosomes support the VAMP3 and STX6 interaction and function as barriers to limit the activity of VAMP3 in autophagic vesicle fusion, thus CEMM deficiency promotes autophagosome biogenesis and doxorubicin resistance in breast tumors.Yin ShiZu YeGuang LuNaidi YangJianbin ZhangLiming WangJianzhou CuiMiguel A. del PozoYihua WuDajing XiaHan-Ming ShenElsevierarticleautophagybreast cancerdoxorubicin resistancecholesterol-enriched membrane micro-domainsCAV1VAMP3Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Therapy: Oncolytics, Vol 23, Iss , Pp 311-329 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autophagy breast cancer doxorubicin resistance cholesterol-enriched membrane micro-domains CAV1 VAMP3 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	autophagy breast cancer doxorubicin resistance cholesterol-enriched membrane micro-domains CAV1 VAMP3 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yin Shi Zu Ye Guang Lu Naidi Yang Jianbin Zhang Liming Wang Jianzhou Cui Miguel A. del Pozo Yihua Wu Dajing Xia Han-Ming Shen Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer
description	Drug resistance has become one of the largest challenges for cancer chemotherapies. Under certain conditions, cancer cells hijack autophagy to cope with therapeutic stress, which largely undermines the chemo-therapeutic efficacy. Currently, biomarkers indicative of autophagy-derived drug resistance remain largely inclusive. Here, we report a novel role of lipid rafts/cholesterol-enriched membrane micro-domains (CEMMs) in autophagosome biogenesis and doxorubicin resistance in breast tumors. We showed that CEMMs are required for the interaction of VAMP3 with syntaxin 6 (STX6, a cholesterol-binding SNARE protein). Upon disruption of CEMM, VAMP3 is released from STX6, resulting in the trafficking of ATG16L1-containing vesicles to recycling endosomes and subsequent autophagosome biogenesis. Furthermore, we found that CEMM marker CAV1 is decreased in breast cancer patients and that the CEMM deficiency-induced autophagy is related to doxorubicin resistance, which is overcome by autophagy inhibition. Taken together, we propose a novel model whereby CEMMs in recycling endosomes support the VAMP3 and STX6 interaction and function as barriers to limit the activity of VAMP3 in autophagic vesicle fusion, thus CEMM deficiency promotes autophagosome biogenesis and doxorubicin resistance in breast tumors.
format	article
author	Yin Shi Zu Ye Guang Lu Naidi Yang Jianbin Zhang Liming Wang Jianzhou Cui Miguel A. del Pozo Yihua Wu Dajing Xia Han-Ming Shen
author_facet	Yin Shi Zu Ye Guang Lu Naidi Yang Jianbin Zhang Liming Wang Jianzhou Cui Miguel A. del Pozo Yihua Wu Dajing Xia Han-Ming Shen
author_sort	Yin Shi
title	Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer
title_short	Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer
title_full	Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer
title_fullStr	Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer
title_full_unstemmed	Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer
title_sort	cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/784d7619203943aa977f70f75746777f
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Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer

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