文章基本信息

标题：Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response
本地全文：下载
作者：Qian Dai ; Xiaolin Liu ; Tao He 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：10
页码：1-20
DOI：10.1016/j.isci.2021.103170
语种：English
出版社：Elsevier
摘要：SummaryTaxane-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 ofangiopoietin like 4(ANGPTL4), a major regulator of human blood lipid profile. Notably, premedication with dexamethasone further enhances the expression ofANGPTL4. 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.Graphical abstractDisplay OmittedHighlights•Cremophor EL, the excipient of chemotherapy drug Taxol, is biologically active•Cremophor EL promotes aerobic glycolysis in cancer and primary human immune cells•Dexamethasone and Cremophor EL may cause dyslipidemia via ANGPTL4 upregulation•Cremophor EL promotes the unfolded protein responseBiological sciences; Molecular biology; Cell biology; Cancer