Pharmacological Targeting of Vacuolar H+-ATPase via Subunit V1G Combats Multidrug-Resistant Cancer

  • Cell Chem Biol. 2020 Nov 19;27(11):1359-1370.e8. doi: 10.1016/j.chembiol.2020.06.011.
Yuezhou Wang  1 ,  Lei Zhang  1 ,  Yanling Wei  1 ,  Wei Huang  1 ,  Li Li  1 ,  An-An Wu  2 ,  Anahita Dastur  3 ,  Patricia Greninger  3 ,  Walter M Bray  4 ,  Chen-Song Zhang  1 ,  Mengqi Li  1 ,  Wenhua Lian  1 ,  Zhiyu Hu  1 ,  Xiaoyong Wang  5 ,  Gang Liu  5 ,  Luming Yao  1 ,  Jih-Hwa Guh  6 ,  Lanfen Chen  1 ,  Hong-Rui Wang  1 ,  Dawang Zhou  1 ,  Sheng-Cai Lin  1 ,  Qingyan Xu  1 ,  Yuemao Shen  7 ,  Jianming Zhang  8 ,  Melissa S Jurica  9 ,  Cyril H Benes  3 ,  Xianming Deng  10
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian 361102, China.
  • 2. State Key Laboratory for Physical Chemistry of Solid Surface, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China; Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen, Fujian, China.
  • 3. Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
  • 4. Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
  • 5. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China.
  • 6. School of Pharmacy, National Taiwan University, Taipei, Taiwan.
  • 7. School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, China.
  • 8. National Translational Research Center Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025 China.
  • 9. Department of Molecular Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, CA 95064, USA.
  • 10. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].
PMID: 32649904 DOI: 10.1016/j.chembiol.2020.06.011
Abstract

Multidrug resistance (MDR) in Cancer remains a major challenge for the success of chemotherapy. Natural products have been a rich source for the discovery of drugs against MDR cancers. Here, we applied high-throughput cytotoxicity screening of an in-house natural product library against MDR SGC7901/VCR cells and identified that the cyclodepsipeptide verucopeptin demonstrated notable antitumor potency. Cytological profiling combined with click chemistry-based proteomics revealed that ATP6V1G directly interacted with verucopeptin. ATP6V1G, a subunit of the vacuolar H+-ATPase (v-ATPase) that has not been previously targeted, was essential for SGC7901/VCR cell growth. Verucopeptin exhibited strong inhibition of both v-ATPase activity and mTORC1 signaling, leading to substantial pharmacological efficacy against SGC7901/VCR cell proliferation and tumor growth in vivo. Our results demonstrate that targeting v-ATPase via its V1G subunit constitutes a unique approach for modulating v-ATPase and mTORC1 signaling with great potential for the development of therapeutics against MDR cancers.

Keywords
V-ATPase; mTORC1 pathway; natural product; target identification.
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