2. Academic Validation
  3. Pharmacological Targeting of Vacuolar H+-ATPase via Subunit V1G Combats Multidrug-Resistant Cancer

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

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: xmdeng@xmu.edu.cn.
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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