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  2. 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.
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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