Metformin facilitates BG45-induced apoptosis via an anti-Warburg effect in cholangiocarcinoma cells
Metformin facilitates BG45-induced apoptosis via an anti-Warburg effect in cholangiocarcinoma cells
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二甲双胍通过抗 Warburg 效应促进胆管癌细胞中 BG45 诱导的细胞凋亡
DOI：
10.3892/or.2018.6275
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发表时间：
2018-04-01
期刊：
影响因子：
4.2
通讯作者：
Zou, Xiaoping
中科院分区：
文献类型：
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作者：
Tang, Dehua;Xu, Lei;Zou, Xiaoping
胆管癌是一种高致死性的恶性肿瘤，诊断较晚，预后差。化疗是大多数患者的唯一治疗策略。与正常细胞相比，即使在有氧条件下，肿瘤细胞也优先将葡萄糖代谢为乳酸。这种代谢改变不仅支持肿瘤细胞的生长和侵袭，而且还促进其化学抗性。本研究的目的是探讨二甲双胍在调节CCA代谢中的作用，以及研究二甲双胍是否可以作为HDAC3抑制剂BG 45的化疗增敏剂，从而具有治疗CCA的潜力。通过生物信息学分析，我们发现代谢异常促进了CCA细胞的增殖。Seahorse XF 96细胞外通量分析仪分析和乳酸产生分析表明，二甲双胍可以作为CCA细胞中的瓦尔堡效应的抑制剂。Western blotting显示二甲双胍降低了LDHA的表达，LDHA在瓦尔堡效应中起关键作用。然而，抑制瓦尔堡效应不足以诱导CCA细胞凋亡。根据我们先前的研究表明HDAC3抑制剂（MI 192）参与CCA凋亡，我们观察到二甲双胍与BG 45（一种新型特异性HDAC3抑制剂）在体外有效地诱导CCA细胞凋亡。此外，体内实验表明，二甲双胍和BG 45的联合治疗显著降低了CCA异种移植模型中的CCA生长。我们的数据显示，用二甲双胍逆转瓦尔堡效应使细胞对HDAC 3抑制剂的抗肿瘤作用敏感。这为使用二甲双胍和BG 45联合作为治疗CCA的新治疗策略提供了依据。
Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA. Through bioinformatic analysis, we found that aberrant metabolism contributed to the proliferation of CCA cells. Seahorse XF96 Extracellular Flux Analyzer analysis and lactate production analysis showed that metformin could act as a suppressor of the Warburg effect in CCA cells. Western blotting showed that metformin decreased the expression of LDHA, which plays a key role in the Warburg effect. However, suppression of the Warburg effect was not sufficient to induce CCA cellular apoptosis. According to our previous research, which showed that an HDAC3 inhibitor (MI192) was involved in CCA apoptosis, we observed that metformin combined with BG45 (a novel specific HDAC3 inhibitor) effectively induced the apoptosis of CCA cells in vitro. Furthermore, in vivo experiments revealed that the combined treatment with metformin and BG45 markedly reduced CCA growth in a CCA xenograft model. Our data revealed that reversing the Warburg effect with metformin sensitizes cells to the antitumor effects of HDAC3 inhibitors. This provides a rationale for using the combination of metformin and BG45 as a new therapeutic strategy in the treatment of CCA.