Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response
Summary: Taxane-based reagents, such as Taxol, Taxotere, and Abraxane, are popular anti-cancer drugs that can differ in their clinical efficacy. This difference is generally attributed to their active pharmaceutical ingredients. Here, we report a serendipitous discovery that Taxol induces metabolic...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-10-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422101138X |
| _version_ | 1818581443586031616 |
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| author | Qian Dai Xiaolin Liu Tao He Chao Yang Jinfeng Jiang Yin Fang Zhoukai Fu Yuan Yuan Shujun Bai Tong Qiu Rutie Yin Ping Ding Jie Chen Qintong Li |
| author_facet | Qian Dai Xiaolin Liu Tao He Chao Yang Jinfeng Jiang Yin Fang Zhoukai Fu Yuan Yuan Shujun Bai Tong Qiu Rutie Yin Ping Ding Jie Chen Qintong Li |
| author_sort | Qian Dai |
| collection | DOAJ |
| description | Summary: Taxane-based reagents, such as Taxol, Taxotere, and Abraxane, are popular anti-cancer drugs that can differ in their clinical efficacy. This difference is generally attributed to their active pharmaceutical ingredients. Here, we report a serendipitous discovery that Taxol induces metabolic dysregulation and unfolded protein response. Surprisingly, these effects of Taxol are entirely dependent on its excipient, Cremophor EL (CrEL). We show that CrEL promotes aerobic glycolysis and in turn results in drastic upregulation of angiopoietin like 4 (ANGPTL4), a major regulator of human blood lipid profile. Notably, premedication with dexamethasone further enhances the expression of ANGPTL4. Consistently, we find that the amplitude and frequency of increase in triglycerides is more prominent in Taxol-treated patients with breast cancer. In addition, we find that CrEL activates the unfolded protein response pathway to trigger proinflammatory gene expression and caspase/gasdermin E-dependent pyroptosis. Finally, we discuss the implications of these results in anti-cancer therapies. |
| first_indexed | 2024-12-16T07:33:35Z |
| format | Article |
| id | doaj.art-70fab6fc86904912ab2f43522fc583ae |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-16T07:33:35Z |
| publishDate | 2021-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-70fab6fc86904912ab2f43522fc583ae2022-12-21T22:39:18ZengElsevieriScience2589-00422021-10-012410103170Excipient of paclitaxel induces metabolic dysregulation and unfolded protein responseQian Dai0Xiaolin Liu1Tao He2Chao Yang3Jinfeng Jiang4Yin Fang5Zhoukai Fu6Yuan Yuan7Shujun Bai8Tong Qiu9Rutie Yin10Ping Ding11Jie Chen12Qintong Li13Departments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Center of Growth, Metabolism and Aging, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaDepartments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Center of Growth, Metabolism and Aging, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaDepartment of Breast Surgery, Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu 610041, ChinaDivisions of Bioinformatics & Immunology, Cunde Therapeutics, Chengdu 610093, ChinaDivisions of Bioinformatics & Immunology, Cunde Therapeutics, Chengdu 610093, ChinaDepartments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Center of Growth, Metabolism and Aging, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaDepartment of Breast Surgery, Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu 610041, ChinaDivisions of Bioinformatics & Immunology, Cunde Therapeutics, Chengdu 610093, ChinaDepartments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Center of Growth, Metabolism and Aging, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaDepartments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Center of Growth, Metabolism and Aging, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaDepartments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Center of Growth, Metabolism and Aging, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, ChinaDivisions of Bioinformatics & Immunology, Cunde Therapeutics, Chengdu 610093, China; Non-coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, China; Corresponding authorDepartment of Breast Surgery, Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu 610041, China; Corresponding authorDepartments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Center of Growth, Metabolism and Aging, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China; Corresponding authorSummary: Taxane-based reagents, such as Taxol, Taxotere, and Abraxane, are popular anti-cancer drugs that can differ in their clinical efficacy. This difference is generally attributed to their active pharmaceutical ingredients. Here, we report a serendipitous discovery that Taxol induces metabolic dysregulation and unfolded protein response. Surprisingly, these effects of Taxol are entirely dependent on its excipient, Cremophor EL (CrEL). We show that CrEL promotes aerobic glycolysis and in turn results in drastic upregulation of angiopoietin like 4 (ANGPTL4), a major regulator of human blood lipid profile. Notably, premedication with dexamethasone further enhances the expression of ANGPTL4. Consistently, we find that the amplitude and frequency of increase in triglycerides is more prominent in Taxol-treated patients with breast cancer. In addition, we find that CrEL activates the unfolded protein response pathway to trigger proinflammatory gene expression and caspase/gasdermin E-dependent pyroptosis. Finally, we discuss the implications of these results in anti-cancer therapies.http://www.sciencedirect.com/science/article/pii/S258900422101138XBiological sciencesMolecular biologyCell biologyCancer |
| spellingShingle | Qian Dai Xiaolin Liu Tao He Chao Yang Jinfeng Jiang Yin Fang Zhoukai Fu Yuan Yuan Shujun Bai Tong Qiu Rutie Yin Ping Ding Jie Chen Qintong Li Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response iScience Biological sciences Molecular biology Cell biology Cancer |
| title | Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response |
| title_full | Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response |
| title_fullStr | Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response |
| title_full_unstemmed | Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response |
| title_short | Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response |
| title_sort | excipient of paclitaxel induces metabolic dysregulation and unfolded protein response |
| topic | Biological sciences Molecular biology Cell biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S258900422101138X |
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