https://scholars.lib.ntu.edu.tw/handle/123456789/564746
標題: | Pharmacological Targeting of Vacuolar H+-ATPase via Subunit V1G Combats Multidrug-Resistant Cancer | 作者: | Wang Y. Zhang L. Wei Y. Huang W. Li L. Wu A.-A. Dastur A. Greninger P. Bray W.M. Zhang C.-S. Li M. Lian W. Hu Z. Wang X. Liu G. Yao L. JIH-HWA GUH Chen L. Wang H.-R. Zhou D. Lin S.-C. Xu Q. Shen Y. Zhang J. Jurica M.S. Benes C.H. Deng X. |
關鍵字: | mTORC1 pathway; natural product; target identification; V-ATPase | 公開日期: | 2020 | 卷: | 27 | 期: | 11 | 起(迄)頁: | 1359-1370 | 來源出版物: | Cell Chemical Biology | 摘要: | 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. ? 2020 Elsevier LtdAlternative strategy for treating multidrug-resistant (MDR) cancer is needed. Wang et al. show that the natural product verucopeptin kills MDR cancer by targeting the ATP6V1G subunit of v-ATPase, which leads to strong inhibition of both v-ATPase activity and mTORC1 signaling. ? 2020 Elsevier Ltd |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85088217071&doi=10.1016%2fj.chembiol.2020.06.011&partnerID=40&md5=bedb3c7d8baba9d9b70edf8f14964383 https://scholars.lib.ntu.edu.tw/handle/123456789/564746 |
ISSN: | 24519456 | DOI: | 10.1016/j.chembiol.2020.06.011 | SDG/關鍵字: | cyclodepsipeptide; proton transporting adenosine triphosphate synthase; unclassified drug; verucopeptin; antineoplastic agent; biological product; depsipeptide; mammalian target of rapamycin complex 1; proton transporting adenosine triphosphate synthase; verucopeptin; animal cell; animal experiment; animal model; antineoplastic activity; antiproliferative activity; Article; cancer resistance; cell proliferation; controlled study; cytotoxicity; drug potency; enzyme activity; enzyme inhibition; enzyme subunit; high throughput screening; human; human cell; in vitro study; in vivo study; lysosome; malignant neoplasm; mouse; mTOR signaling; multidrug resistance; nonhuman; priority journal; protein interaction; protein targeting; signal transduction; tumor growth; animal; Bagg albino mouse; cell culture; cell survival; chemistry; drug effect; drug resistance; drug screening; experimental neoplasm; female; male; metabolism; multidrug resistance; nude mouse; pathology; protein subunit; proteomics; synthesis; tumor cell line; Animals; Antineoplastic Agents; Biological Products; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Depsipeptides; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Protein Subunits; Proteomics; Vacuolar Proton-Translocating ATPases |
顯示於: | 藥學系 |
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