Imiquimod Accelerated Antitumor Response by Targeting Lysosome Adaptation in Skin Cancer Cells

Shu Hao Chang, Chun Ying Wu, Kai Cheng Chuang, Shi Wei Huang, Zheng Yi Li, Sin Ting Wang, Zi Lun Lai, Cheng Chung Chang, Yi Ju Chen, Tak Wah Wong, Jun Kai Kao, Jeng Jer Shieh

Research output: Contribution to journalArticlepeer-review

Abstract

Lysosomal adaptation is a cellular physiological process in which the number and function of lysosomes are regulated at the transcriptional and post-transcriptional levels in response to extracellular and/or intracellular cues or lysosomal damage. Imiquimod (IMQ), a synthetic toll-like receptor 7 ligand with hydrophobic and weak basic properties, exhibits both antitumor and antiviral activity against various skin malignancies as a clinical treatment. Interestingly, IMQ has been suggested to be highly concentrated in the lysosomes of plasmacytoid dendritic cells, indicating that IMQ could modulate lysosome function after sequestration in the lysosome. In this study, we found that IMQ not only induced lysosomal membrane permeabilization and dysfunction but also increased lysosome biogenesis to achieve lysosomal adaptation in cancer cells. IMQ-induced ROS production but not lysosomal sequestration of IMQ was the major cause of lysosomal adaptation. Moreover, IMQ-induced lysosomal adaptation occurred through lysosomal calcium ion release and activation of the calcineurin/TFEB axis to promote lysosome biogenesis. Finally, depletion of TFEB sensitized skin cancer cells to IMQ-induced apoptosis in vitro and in vivo. In summary, a disruption of lysosomal adaptation might represent a therapeutic strategy for synergistically enhancing the cytotoxicity of IMQ in skin cancer cells.

Original languageEnglish
Pages (from-to)2219-2228.e8
JournalJournal of Investigative Dermatology
Volume141
Issue number9
DOIs
Publication statusPublished - 2021 Sep

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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