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

Cell chemical biology (2020-07-11)
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
RÉSUMÉ

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.

MATÉRIAUX
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Description du produit

Sigma-Aldrich
Isothiocyanate-dextrane marqué à la fluorescence, average mol wt 10,000
Sigma-Aldrich
Lysosome Isolation Kit, sufficient for 25 g (tissue), sufficient for 20 mL (packed cells), enrichment of lysosomes from tissues and packed cells
Sigma-Aldrich
1,3-Propylene sulfite, 99%
Dounce tissue grinder pestle, Large clearance, working volume 7 mL