Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S237277052100142X |
| _version_ | 1819095407416836096 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-21T23:42:49Z |
| format | Article |
| id | doaj.art-784d7619203943aa977f70f75746777f |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-21T23:42:49Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-784d7619203943aa977f70f75746777f2022-12-21T18:46:12ZengElsevierMolecular Therapy: Oncolytics2372-77052021-12-0123311329Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancerYin Shi0Zu Ye1Guang Lu2Naidi Yang3Jianbin Zhang4Liming Wang5Jianzhou Cui6Miguel A. del Pozo7Yihua Wu8Dajing Xia9Han-Ming Shen10Department of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 119077, Singapore; Corresponding author: Yin Shi, Department of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 119077, Singapore; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USADepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 119077, SingaporeDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 119077, Singapore; Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University, Nanjing, Jiangsu Province 211800, ChinaDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 119077, SingaporeDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 119077, Singapore; School of Biomedical Science, Hunan University, Changsha, Hunan, ChinaDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 119077, SingaporeIntegrin Signaling Laboratory, Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, SpainDepartment of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaDepartment of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 119077, Singapore; Faculty of Health Sciences, University of Macau, Macau SAR 999078, China; Corresponding author: Han-Ming Shen, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 119077 Singapore.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.http://www.sciencedirect.com/science/article/pii/S237277052100142Xautophagybreast cancerdoxorubicin resistancecholesterol-enriched membrane micro-domainsCAV1VAMP3 |
| spellingShingle | 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-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer Molecular Therapy: Oncolytics autophagy breast cancer doxorubicin resistance cholesterol-enriched membrane micro-domains CAV1 VAMP3 |
| title | Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer |
| title_full | Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer |
| title_fullStr | Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer |
| title_full_unstemmed | Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer |
| title_short | Cholesterol-enriched membrane micro-domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer |
| title_sort | cholesterol enriched membrane micro domain deficiency induces doxorubicin resistance via promoting autophagy in breast cancer |
| topic | autophagy breast cancer doxorubicin resistance cholesterol-enriched membrane micro-domains CAV1 VAMP3 |
| url | http://www.sciencedirect.com/science/article/pii/S237277052100142X |
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