2. Academic Validation
  3. Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy

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

  • EMBO Mol Med. 2022 Feb 7;14(2):e14903. doi: 10.15252/emmm.202114903.
Zhe Zhang  # 1 2,  Siyuan Qin  # 2,  Yan Chen  # 2,  Li Zhou 2,  Mei Yang 2,  Yongquan Tang 3,  Jing Zuo 2,  Jian Zhang 4 5,  Atsushi Mizokami 6,  Edouard C Nice 7,  Hai-Ning Chen 8,  Canhua Huang 2,  Xiawei Wei 1
Affiliations

Affiliations

  • 1 Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
  • 3 Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China.
  • 4 School of Medicine, Southern University of Science and Technology Shenzhen, Guangdong, China.
  • 5 Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, China.
  • 6 Department of Urology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
  • 7 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic, Australia.
  • 8 Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
  • # Contributed equally.
PMID: 35023619 DOI: 10.15252/emmm.202114903
Abstract

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.

Keywords

NPC1L1; cancer therapy; drug-tolerant persister state; multidrug resistance; oxidative stress.

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