Synergistic combination of DT-13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC-823 cells via NM IIA/EGFR/HK II axis
Synergistic combination of DT-13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC-823 cells via NM IIA/EGFR/HK II axis
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DT-13和拓扑替康协同组合通过NM IIA/EGFR/HK II轴抑制人胃癌BGC-823细胞的有氧糖酵解
DOI：
10.1111/jcmm.14523
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发表时间：
2019
影响因子：
5.3
通讯作者：
Sun Li
中科院分区：
文献类型：
--
作者：
Yu Xiao-Wen;Wei D;an;Gao Ying-Sheng;Du Hong-Zhi;Yu Bo-Yang;Li Rui-Ming;Qian Chang-Min;Luo Xue-Jun;Yuan Sheng-Tao;Wang Jun-Song;Sun Li
与我们之前的研究中各自的效果相比，DT-13联合拓扑替康（TPT）在小鼠皮下异种移植模型中表现出更强的抗肿瘤作用。在这里，我们进一步观察了小鼠原位异种移植模型中的协同效应。代谢组学分析表明，DT-13联合TPT可减轻肿瘤引起的代谢紊乱，并在体内和体外协同抑制有氧糖酵解相关酶的活性。机理研究表明，与TPT或DT-13单药治疗相比，联合治疗通过非肌肉肌球蛋白IIA（NM IIA）诱导的EGFR内吞作用促进表皮生长因子受体（EGFR）降解，进一步抑制己糖激酶II（HK II）的活性，最终更有效地促进有氧糖酵解抑制活性。联合疗法还抑制 HK II 与线粒体的特异性结合。当使用 NM II 抑制剂 (‐)002Dblebbistatin 或 MYH-9 shRNA 时，DT-13 和 TPT 对 BGC-823 细胞中有氧糖酵解的协同抑制作用被消除。免疫组织化学分析显示，联合疗法选择性上调 NM IIA，同时特异性下调 p-CREB、EGFR 和 HK II。总的来说，这些发现表明该方案具有显着的临床意义，值得进一步研究。
DT‐13 combined with topotecan (TPT) showed stronger antitumour effects in mice subcutaneous xenograft model compared with their individual effects in our previous research. Here, we further observed the synergistically effect in mice orthotopic xenograft model. Metabolomics analysis showed DT‐13 combined with TPT alleviated metabolic disorders induced by tumour and synergistically inhibited the activity of the aerobic glycolysis‐related enzymes in vivo and in vitro. Mechanistic studies revealed that the combination treatment promoted epidermal growth factor receptor (EGFR) degradation through non‐muscle myosin IIA (NM IIA)‐induced endocytosis of EGFR, further inhibited the activity of hexokinase II (HK II), and eventually promoted the aerobic glycolysis inhibition activity more efficiently compared with TPT or DT‐13 monotherapy. The combination therapy also inhibited the specific binding of HK II to mitochondria. When using the NM II inhibitor (‐)002Dblebbistatin or MYH‐9 shRNA, the synergistic inhibition effect of DT‐13 and TPT on aerobic glycolysis was eliminated in BGC‐823 cells. Immunohistochemical analysis revealed selective up‐regulation of NM IIA while specific down‐regulation of p‐CREB, EGFR, and HK II by the combination therapy. Collectively, these findings suggested that this regimen has significant clinical implications, warranted further investigation.