Toosendanin, a novel potent vacuolar-type H+-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy

Yu Dong, Guoyuan Zhu, Sheng Fang Wang, Kristine A. Keon, John L. Rubinstein, Si Xin Zeng, Shuang Zhang, Qiu Ling Chen, Jing Fu, Min Li, Han Ming Shen, Jin Jian Lu, Xiu Ping Chen, Jia Hong Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Macroautophagy/autophagy is the process of self-digestion through the lysosomes; it disassembles unnecessary or dysfunctional long-lived proteins and damaged organelles for the recycling of biomacromolecules. Unfortunately, cancer cells can hijack this mechanism to survive under metabolic stress or develop drug resistance during chemotherapy. Increasing evidence indicates that the combination of autophagy inhibition and chemotherapy is a promising cancer treatment strategy. However, effective autophagy inhibitors with satisfied potency, bioavailability, and clearly-defined drug targets are still rare. Here, we report the identification of a potent autophagy inhibitor toosendanin which can effectively block autophagosome maturation, causing the accumulation of autophagy substrates in multiple cancer cells. Toosendanin did not inhibit the fusion process between autophagosome and lysosome but elevated lysosomal pH and impaired lysosomal enzymes activity. Using rat liver lysosome fraction and purified yeast V-ATPase, we found that toosendanin directly inhibited V-ATPase activity. By applying cellular thermal shift assay (CETSA), immunoprecipitation-coupled LC-MS/MS analysis, and biotin-toosendanin pull-down assay, we confirmed the direct binding between toosendanin and V-ATPase. Furthermore, toosendanin blocked chemotherapy-induced protective autophagy in cultured cancer cells and xenograft tumor tissues to significantly enhance anti-cancer activity. These results suggest that toosendanin has the potential to be developed into an anti-cancer drug by blocking chemotherapy-induced protective autophagy.

Original languageEnglish
Pages (from-to)2684-2702
Number of pages19
JournalInternational Journal of Biological Sciences
Volume18
Issue number7
DOIs
Publication statusPublished - Mar 2022

Scopus Subject Areas

  • Applied Microbiology and Biotechnology
  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Cell Biology
  • Developmental Biology

User-Defined Keywords

  • anti-cancer effect
  • autophagy inhibitor
  • protective autophagy
  • toosendanin
  • V-ATPase inhibitor
  • Triterpenes
  • Humans
  • Neoplasms/drug therapy
  • Rats
  • Autophagy
  • Tandem Mass Spectrometry
  • Antineoplastic Agents/pharmacology
  • Vacuolar Proton-Translocating ATPases/metabolism
  • Animals
  • Chromatography, Liquid
  • Adenosine Triphosphatases/metabolism

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