Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy
Abstract Entering a drug‐tolerant persister (DTP) state of cancer cells is a transient self‐adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug‐resistant (MDR) cancer cells as a tolerance respons...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114903 |
| _version_ | 1797288205956939776 |
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| author | Zhe Zhang Siyuan Qin Yan Chen Li Zhou Mei Yang Yongquan Tang Jing Zuo Jian Zhang Atsushi Mizokami Edouard C Nice Hai‐Ning Chen Canhua Huang Xiawei Wei |
| author_facet | Zhe Zhang Siyuan Qin Yan Chen Li Zhou Mei Yang Yongquan Tang Jing Zuo Jian Zhang Atsushi Mizokami Edouard C Nice Hai‐Ning Chen Canhua Huang Xiawei Wei |
| author_sort | Zhe Zhang |
| collection | DOAJ |
| description | Abstract Entering a drug‐tolerant persister (DTP) state of cancer cells is a transient self‐adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug‐resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA‐seq revealed that these cells partially prevented chemotherapy‐triggered oxidative stress by promoting NPC1L1‐regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the −205 to −215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple‐combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti‐tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy. |
| first_indexed | 2024-03-07T18:45:00Z |
| format | Article |
| id | doaj.art-fba468bc75374ae3a4016b9dc92a4961 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:45:00Z |
| publishDate | 2022-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-fba468bc75374ae3a4016b9dc92a49612024-03-02T02:46:10ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-02-01142n/an/a10.15252/emmm.202114903Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapyZhe Zhang0Siyuan Qin1Yan Chen2Li Zhou3Mei Yang4Yongquan Tang5Jing Zuo6Jian Zhang7Atsushi Mizokami8Edouard C Nice9Hai‐Ning Chen10Canhua Huang11Xiawei Wei12Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics, West China Hospital Sichuan University Chengdu ChinaState Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu ChinaState Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu ChinaState Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu ChinaState Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu ChinaDepartment of Pediatric Surgery West China Hospital Sichuan University Chengdu ChinaState Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu ChinaSchool of Medicine Southern University of Science and Technology Shenzhen Guangdong ChinaDepartment of Urology Graduate School of Medical Sciences Kanazawa University Kanazawa JapanDepartment of Biochemistry and Molecular Biology Monash University Clayton Vic AustraliaDepartment of Gastrointestinal Surgery State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu ChinaState Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu ChinaLaboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics, West China Hospital Sichuan University Chengdu ChinaAbstract Entering a drug‐tolerant persister (DTP) state of cancer cells is a transient self‐adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug‐resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA‐seq revealed that these cells partially prevented chemotherapy‐triggered oxidative stress by promoting NPC1L1‐regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the −205 to −215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple‐combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti‐tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy.https://doi.org/10.15252/emmm.202114903cancer therapydrug‐tolerant persister statemultidrug resistanceNPC1L1oxidative stress |
| spellingShingle | Zhe Zhang Siyuan Qin Yan Chen Li Zhou Mei Yang Yongquan Tang Jing Zuo Jian Zhang Atsushi Mizokami Edouard C Nice Hai‐Ning Chen Canhua Huang Xiawei Wei Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy EMBO Molecular Medicine cancer therapy drug‐tolerant persister state multidrug resistance NPC1L1 oxidative stress |
| title | Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy |
| title_full | Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy |
| title_fullStr | Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy |
| title_full_unstemmed | Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy |
| title_short | Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy |
| title_sort | inhibition of npc1l1 disrupts adaptive responses of drug tolerant persister cells to chemotherapy |
| topic | cancer therapy drug‐tolerant persister state multidrug resistance NPC1L1 oxidative stress |
| url | https://doi.org/10.15252/emmm.202114903 |
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