通过 V1G 亚基靶向空泡质子泵（Vacuolar H-ATPase）对抗多药耐药性癌症。
Pharmacological Targeting of Vacuolar H-ATPase via Subunit V1G Combats Multidrug-Resistant Cancer.
机构信息
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.
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.
出版信息
Cell Chem Biol. 2020 Nov 19;27(11):1359-1370.e8. doi: 10.1016/j.chembiol.2020.06.011. Epub 2020 Jul 9.
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.
癌症的多药耐药（MDR）仍然是化疗成功的主要挑战。天然产物一直是发现针对 MDR 癌症药物的丰富来源。在这里，我们应用高通量细胞毒性筛选方法对内部天然产物库进行筛选，以鉴定对 MDR SGC7901/VCR 细胞具有显著抗肿瘤活性的化合物，结果表明环二肽 verucopeptin 具有显著的抗肿瘤活性。细胞形态学分析与基于点击化学的蛋白质组学研究揭示了 ATP6V1G 与 verucopeptin 直接相互作用。ATP6V1G 是液泡 H+-ATP 酶（v-ATPase）的一个亚基，以前尚未作为靶点，对于 SGC7901/VCR 细胞的生长是必需的。Verucopeptin 对 v-ATPase 活性和 mTORC1 信号通路具有强烈的抑制作用，从而显著抑制 SGC7901/VCR 细胞的增殖，并在体内抑制肿瘤生长。我们的研究结果表明，通过 V1G 亚基靶向 v-ATPase 是一种独特的调节 v-ATPase 和 mTORC1 信号通路的方法，为开发针对 MDR 癌症的治疗方法提供了巨大潜力。
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