Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response

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

doi:10.1016/j.isci.2021.103170

Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response

iScience. 2021 Sep 25;24(10):103170. doi: 10.1016/j.isci.2021.103170. eCollection 2021 Oct 22.

Authors

Qian Dai¹, Xiaolin Liu¹, Tao He², Chao Yang³, Jinfeng Jiang³, Yin Fang¹, Zhoukai Fu², Yuan Yuan³, Shujun Bai¹, Tong Qiu¹, Rutie Yin¹, Ping Ding^{3

4}, Jie Chen², Qintong Li¹

Affiliations

¹ Departments 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.
² Department of Breast Surgery, Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu 610041, China.
³ Divisions of Bioinformatics & Immunology, Cunde Therapeutics, Chengdu 610093, China.
⁴ Non-coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, China.

Abstract

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.

Keywords: Biological sciences; Cancer; Cell biology; Molecular biology.