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

Yuezhou Wang; Lei Zhang; Yanling Wei; Wei Huang; Li Li; An-An Wu; Anahita Dastur; Patricia Greninger; Walter M Bray; Chen-Song Zhang; Mengqi Li; Wenhua Lian; Zhiyu Hu; Xiaoyong Wang; Gang Liu; Luming Yao; Jih-Hwa Guh; Lanfen Chen; Hong-Rui Wang; Dawang Zhou; Sheng-Cai Lin; Qingyan Xu; Yuemao Shen; Jianming Zhang; Melissa S Jurica; Cyril H Benes; Xianming Deng

doi:10.1016/j.chembiol.2020.06.011

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. Epub 2020 Jul 9.

Authors

Yuezhou Wang¹, Lei Zhang¹, Yanling Wei¹, Wei Huang¹, Li Li¹, An-An Wu², Anahita Dastur³, Patricia Greninger³, Walter M Bray⁴, Chen-Song Zhang¹, Mengqi Li¹, Wenhua Lian¹, Zhiyu Hu¹, Xiaoyong Wang⁵, Gang Liu⁵, Luming Yao¹, Jih-Hwa Guh⁶, Lanfen Chen¹, Hong-Rui Wang¹, Dawang Zhou¹, Sheng-Cai Lin¹, Qingyan Xu¹, Yuemao Shen⁷, Jianming Zhang⁸, Melissa S Jurica⁹, Cyril H Benes³, Xianming Deng¹⁰

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Biological Products / chemical synthesis
Biological Products / chemistry
Biological Products / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Depsipeptides / chemical synthesis
Depsipeptides / chemistry
Depsipeptides / pharmacology*
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Female
Humans
Male
Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Protein Subunits / drug effects
Proteomics
Vacuolar Proton-Translocating ATPases / antagonists & inhibitors*
Vacuolar Proton-Translocating ATPases / metabolism

Substances

Antineoplastic Agents
Biological Products
Depsipeptides
Protein Subunits
verucopeptin
Mechanistic Target of Rapamycin Complex 1
Vacuolar Proton-Translocating ATPases