期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 18, 期 7, 页码 2684-2702出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.71041
关键词
toosendanin; V-ATPase inhibitor; autophagy inhibitor; protective autophagy; anti-cancer effect
资金
- Science and Technology Development Fund, Macau SAR [0110/2018/A3, 0128/2019/A3]
- University of Macau [MYRG2019-00129-ICMS]
- Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab) [2020B1212030006]
In this study, a potent autophagy inhibitor called toosendanin was identified, which effectively blocked autophagosome maturation and caused the accumulation of autophagy substrates in various cancer cells. Additionally, toosendanin directly inhibited V-ATPase activity and enhanced anti-cancer activity by blocking chemotherapy-induced protective autophagy.
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.
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