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
复制标题
通过亚基 V1G 靶向液泡 H -ATP 酶可对抗多重耐药癌症
DOI：
10.1016/j.chembiol.2020.06.011
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发表时间：
2020
影响因子：
8.6
通讯作者：
X
中科院分区：
文献类型：
--
作者：
Wang Yuezhou;Zhang Lei;Wei Yanling;Huang Wei;Li Li;Wu An-an;Dastur Anahita;Greninger Patricia;Bray Walter M.;Zhang Chen-Song;Li Mengqi;Lian Wenhua;Hu Zhiyu;Wang Xiaoyong;Liu Gang;Yao Luming;Guh Jih-Hwa;Chen Lanfen;Wang Hong-Rui;Zhou Dawang;Lin Sheng-Cai;X
肿瘤的多药耐药(MDR)仍然是化疗成功的主要挑战。天然产品一直是发现抗多药耐药癌症药物的丰富来源。在这里，我们应用了内部天然产物文库对MDR SGC7901/VCR细胞的高通量细胞毒性筛选，并鉴定了环磷脂肽具有显著的抗肿瘤活性。细胞学分析结合基于点击化学的蛋白质组学显示ATP6V1G直接与疣蛋白相互作用。ATP6V1G是空泡H+-ATPase(v-ATPase)的一个亚基，对SGC7901/VCR细胞的生长至关重要。Verucopeptin对v-ATPase活性和mTORC1信号通路都有很强的抑制作用，对SGC7901/VCR细胞的增殖和体内肿瘤生长具有显著的药理作用。我们的结果表明，通过其V1G亚基靶向v-ATPase构成了一种独特的调节v-ATPase和mTORC1信号的方法，在抗MDR癌症的治疗方面具有巨大的潜力。
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 growthin 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.