Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation.
Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation.
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紫草素通过抑制 PKM2 介导的有氧糖酵解和 STAT3 磷酸化来抑制 ESCC 肿瘤生长
DOI：
10.7150/jca.58494
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发表时间：
2021
影响因子：
3.9
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Zhang Q;Liu Q;Zheng S;Liu T;Yang L;Han X;Lu X
背景：紫草素是丙酮酸激酶2（PKM2）的小分子抑制剂，已被证明在多种癌症中发挥抗肿瘤作用。然而，紫草素在食管鳞状细胞癌（ESCC）中的具体作用及相关调控机制尚未明确。材料和方法：通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑 (MTT) 测定评估细胞活力。使用相应的测定试剂盒测量葡萄糖消耗、乳酸产生、糖酵解中间体和丙酮酸激酶酶活性。构建患者来源的异种移植（PDX）模型来观察紫草素的体内抗ESCC作用。通过蛋白质印迹评估 ESCC 组织中的 PKM2、p-PKM2、信号转导子和转录激活子 3 (STAT3)、p-STAT3、葡萄糖转运蛋白 1 (GLUT1) 和己糖激酶 2 (HK2)。基于 PDX，通过免疫组织化学 (IHC) 评估 ESCC 组织中 PKM2、p-PKM2、p-STAT3、GLUT1 和 HK2 的表达。结果：与对照组相比，紫草素能有效抑制细胞增殖，且呈剂量依赖性和时间依赖性。糖酵解检测表明紫草素抑制葡萄糖消耗、乳酸产生、糖酵解中间体和丙酮酸激酶酶活性。此外，紫草素不仅能抑制ESCC的生长，还能降低体内p-PKM2和p-STAT3的表达。最后，紫草素抑制与糖酵解相关的GLUT1和HK2蛋白的表达。结论：紫草素通过抑制PKM2介导的有氧糖酵解、调节PKM2/STAT3信号通路，在ESCC中具有显着的抗肿瘤作用。
Background: Shikonin, a small molecule inhibitor of pyruvate kinase 2 (PKM2), has been demonstrated to play the antitumor effect in various cancers. However, the specific effects and related regulatory mechanism of Shikonin in esophageal squamous cell carcinoma (ESCC) have not been clearly declared. Materials and methods: Cell viability was valued through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Glucose consumption, lactate production, glycolytic intermediates and pyruvate kinase enzymatic activity were measured using corresponding assay kits. Patient-derived xenograft (PDX) models were constructed to observe the anti-ESCC effect of Shikonin in vivo. PKM2, p-PKM2, signal transducer and activator of transcription 3 (STAT3), p-STAT3, glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) in ESCC tissues were assessed by western blot. The expression of PKM2, p-PKM2, p-STAT3, GLUT1 and HK2 was assessed by immunohistochemistry (IHC) in ESCC tissue based on PDXs. Results: Shikonin effectively inhibited cell proliferation in dose-dependent and time-dependent manner compared with the control group. The detection of glycolysis showed that Shikonin suppressed the glucose consumption, lactate production, glycolytic intermediates and pyruvate kinase enzymatic activity. Furthermore, Shikonin not only inhibited the growth of ESCC, but also decreased the expression of p-PKM2 and p-STAT3 in vivo. Finally, Shikonin suppressed the expression of GLUT1 and HK2 proteins which are related to glycolysis. Conclusion: Shikonin has a significant antitumor effect in the ESCC by suppressing PKM2 mediated aerobic glycolysis and regulating PKM2/STAT3 signal pathway.
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DOI：
10.1111/liv.14728
发表时间：
2021-03
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
--
作者：
Prawira A;Le TBU;Vu TC;Huynh H
通讯作者：
Huynh H
影响因子：
--
作者：
He X;Du S;Lei T;Li X;Liu Y;Wang H;Tong R;Wang Y
通讯作者：
Wang Y
影响因子：
2.9
作者：
Du, Wenzhen;Hao, Xiaohong;Liu, Jie
通讯作者：
Liu, Jie
GLUT1 调节前列腺癌中的细胞糖酵解和增殖
影响因子：
2.8
作者：
Xiao, Hengjun;Wang, Jun;Chen, Jun
通讯作者：
Chen, Jun
影响因子：
3.8
作者：
Fan C;Zhang X;Upton Z
通讯作者：
Upton Z