Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL.
Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL.
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DOI：
10.1186/s12935-021-02330-y
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发表时间：
2021-11-24
影响因子：
5.8
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Zhang S;Hua Z;Ba G;Xu N;Miao J;Zhao G;Gong W;Liu Z;Thiele CJ;Li Z
神经母细胞瘤（NB）是一种常见的儿童实体恶性肿瘤，与预后不良。虽然新型小分子化合物二甲基氨基甲叉菜胶（DMAMCL）已被证明在一些肿瘤中诱导细胞死亡，但对其在NB中的作用知之甚少。我们研究了DMAMCL对四种NB细胞系（NPG，AS，KCNR，BE 2）的作用。分别使用Incucyte ZOOM、CCK-8测定、Annexin V-PE/7-AAD流式细胞术和Seahorse XFe 96检测细胞融合、存活、凋亡和糖酵解。使用CompuSyn评估药剂之间的协同效应，并使用异种移植小鼠模型评估DMAMCL的体内效应。使用过表达质粒或siRNA上调和下调磷酸果糖激酶-1，肝型（PFKL）表达。当作为单一药物给药时，DMAMCL以时间和剂量依赖性方式降低细胞增殖，增加SubG 1期细胞的百分比，并在体外诱导细胞凋亡，以及在体内抑制肿瘤生长并延长荷瘤小鼠（NGP，BE 2）的生存期。此外，DMAMCL与依托泊苷或顺铂在体外联合使用时产生协同作用，与依托泊苷在体内联合使用时，与单独使用任何一种药物相比，显示出更高的抗肿瘤作用。从机制上讲，DMAMCL通过减少葡萄糖消耗、乳酸排泄和ATP产生，以及在体外和体内减少关键糖酵解酶PFKL的表达来抑制有氧糖酵解。此外，PFKL过表达减弱DMAML诱导的细胞死亡，而PFKL沉默促进NB细胞死亡。本研究结果表明，DMAMCL在体外和体内均通过抑制有氧糖酵解对NB具有抗肿瘤作用，PFKL可能是DMAMCL在NB中的潜在靶点。在线版本包含补充材料，可通过10.1186/s12935-021-02330-y获得。
Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB. The online version contains supplementary material available at 10.1186/s12935-021-02330-y.
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