Pharmacological Targeting of Vacuolar H+-ATPase via Subunit V1G Combats Multidrug-Resistant Cancer.
Cell Chem Biol
; 27(11): 1359-1370.e8, 2020 11 19.
Article
em En
| MEDLINE
| ID: mdl-32649904
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.
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Base de dados:
MEDLINE
Assunto principal:
Produtos Biológicos
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Resistência a Múltiplos Medicamentos
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Resistencia a Medicamentos Antineoplásicos
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ATPases Vacuolares Próton-Translocadoras
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Depsipeptídeos
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Antineoplásicos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article