Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy

• Published in: EMBO molecular medicine Vol. 14; no. 2; pp. e14903 - n/a
• Main Authors: Zhang, Zhe, Qin, Siyuan, Chen, Yan, Zhou, Li, Yang, Mei, Tang, Yongquan, Zuo, Jing, Zhang, Jian, Mizokami, Atsushi, Nice, Edouard C, Chen, Hai‐Ning, Huang, Canhua, Wei, Xiawei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-02-2022; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Animals; Antibiotics; Antineoplastic Agents - pharmacology; Apoptosis; Cancer; Cancer therapies; cancer therapy; Chemotherapy; DNA methylation; Drug delivery systems; Drug resistance; drug‐tolerant persister state; EMBO03; Epigenetics; Gene expression; Gene regulation; Genotype & phenotype; Homeostasis; Membrane Transport Proteins; Mice; multidrug resistance; Multidrug resistant organisms; NPC1L1; Oxidative stress; Phenotypes; Transcription; Tumors; Verapamil; Vitamin E; cancer therapy; multidrug resistance; drug‐tolerant persister state; NPC1L1; oxidative stress; drug-tolerant persister state
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202114903

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.
Synopsis
Drug‐tolerant persister (DTP) state is a driver of therapy failure and cancer relapse. This study identified a key role for NPC1L1 in multidrug‐resistant (MDR) cancer cells with the DTP state, where NPC1L1 orchestrated a redox signaling against the harsh environment caused by cancer therapy.
MDR cancer cells possess a stronger capacity to enter the DTP state than the non‐resistant cancer cells.
NPC1L1 is a key supporter of the DTP state to counter therapy‐induced oxidative stress in MDR cancer cells.
NPC1L1 inhibition interrupts the uptake of vitamin E and cholesterol, triggering lipid ROS accumulation and consequent lipotoxicity during chemotherapeutic agents/verapamil treatment in MDR cancer cells.
A combination of chemotherapeutic agents, verapamil, and NPC1L1 inhibitor ezetimibe exerts a significant anti‐tumor effect and prevents tumor recurrence in mice.
Graphical Abstract
Drug‐tolerant persister (DTP) state is a driver of therapy failure and cancer relapse. This study identified a key role for NPC1L1 in multidrug‐resistant (MDR) cancer cells with the DTP state, where NPC1L1 orchestrated a redox signaling against the harsh environment caused by cancer therapy.