Open AccessInhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy
Author(s) -
Zhang Zhe,
Qin Siyuan,
Chen Yan,
Zhou Li,
Yang Mei,
Tang Yongquan,
Zuo Jing,
Zhang Jian,
Mizokami Atsushi,
Nice Edouard C,
Chen HaiNing,
Huang Canhua,
Wei Xiawei
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114903
Subject(s) - ezetimibe , verapamil , cancer cell , multidrug tolerance , cancer research , pharmacology , cancer , biology , chemistry , biochemistry , medicine , cholesterol , genetics , biofilm , bacteria , calcium
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.