Physapubescin I from husk tomato suppresses SW1990 cancer cell growth by targeting kidney-type glutaminase
Physapubescin I from husk tomato suppresses SW1990 cancer cell growth by targeting kidney-type glutaminase
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来自带壳番茄的 Physapubescin I 通过靶向肾型谷氨酰胺酶抑制 SW1990 癌细胞生长
DOI：
10.1016/j.bioorg.2019.103186
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发表时间：
2019
影响因子：
5.1
通讯作者：
Li Hua
中科院分区：
文献类型：
--
作者：
Yang Kai-Yin;Wu Can-Rong;Zheng Meng-Zhu;Tang Ruo-Tian;Li Xing-Zhou;Chen Li-Xia;Li Hua
肾型谷氨酰胺酶(KGA)催化谷氨酰胺水解物为谷氨酸提供能量，在许多癌症中过表达，被认为是治疗癌症的新靶点。竹黄素I是从食用草本植物毛酸浆的果实中分离得到的，通过结构虚拟配体筛选，被预测为一种潜在的KGA抑制剂。酶抑制实验、微量热电泳法(MST)和细胞热漂移实验(CETSA)都证明了Phyapubescin I靶向KGA的高效和特异性。EDU增殖实验、Hoechst 33258染色和细胞毒实验表明，与已知的KgA抑制剂BPTES相比，Physiapubescin I能更有效地抑制癌细胞的增殖和促进细胞凋亡。SiRNA敲除KgA可降低Phyapubescin I对SW1990细胞的抑制作用。同时，根癌毒素I可降低SW1990细胞谷氨酰胺代谢，增加细胞内谷氨酰胺水平，相应减少谷氨酸及其下游代谢产物，这可能是其抑制肿瘤细胞增殖、促进细胞凋亡的机制之一。在SW1990异种移植小鼠模型中，藻黄素I也显示出显著的肿瘤生长抑制和低毒。总的来说，通过靶向KGA，Physapubescin I可能成为潜在的候选药物或癌症治疗的先导化合物。
Kidney-type glutaminase (KGA), catalyzing the hydrolysis of glutamine to glutamate for energy supply, is over-expressed in many cancers and has been regarded as a new therapeutic target for cancers. Physapubescin I was isolated from the fruits of the edible herbPhysalis pubescensL., commonly named as “husk tomato or hairy groundcherry”, and was predicted to be a potential KGA inhibitor through structure-based virtual ligand screening. Enzyme inhibition assays, microscale thermophoresis (MST) and cellular thermal shift assay (CETSA) experiments have demonstrated the high efficiency and specificity of physapubescin I targeting KGA. EdU proliferation, Hoechst 33258 staining and cytotoxicity assays indicated that physapubescin I could inhibit cancer cell proliferation and promote apoptosis more effectively than the known KGA inhibitor, BPTES. Knockdown of KGA by siRNA reduced the inhibition of physapubescin I to SW1990 cells. Meanwhile, physapubescin I impaired glutamine metabolism in SW1990 cells with increasing intracellular level of glutamine, and correspondingly decreasing glutamate and its downstream metabolites, which may account for its inhibition of cancer cell proliferation and proapoptosis. Physapubescin I also showed significant tumor growth inhibition and low toxicity in a SW1990 xenograft mouse model. Collectively, physapubescin I may serve as a potential drug candidate or lead compound for cancer therapy by targeting KGA.