Regulation of AMPK-related glycolipid metabolism imbalances redox homeostasis and inhibits anchorage independent growth in human breast cancer cells.
Regulation of AMPK-related glycolipid metabolism imbalances redox homeostasis and inhibits anchorage independent growth in human breast cancer cells.
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AMPK 相关糖脂代谢的调节会导致氧化还原稳态失衡，并抑制人类乳腺癌细胞的贴壁独立生长。
DOI：
10.1016/j.redox.2018.04.016
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发表时间：
2018-07
期刊：
影响因子：
11.4
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Yang L;He Z;Yao J;Tan R;Zhu Y;Li Z;Guo Q;Wei L
乳腺癌是世界上最致命的肿瘤之一，其中15%为三阴性乳腺癌(TNBCs)，转移率高，生存率低。失巢抵抗是肿瘤转移过程中的一个关键过程，通常伴随着代谢重排。在本研究中，我们建立了MDA-MB-231细胞的非锚定生长模型，并研究了其代谢和氧化还原动态平衡的变化。结果表明，在分离生长过程中，MDA-MB-231细胞倾向于通过脂肪酸氧化(FAO)而不是糖酵解产生ATP。葡萄糖被用于磷酸戊糖途径(PPP)以维持氧化还原平衡。此外，我们还发现合成的黄酮衍生物GL-V9在体外对TNBCs的贴壁非依赖性生长有明显的抑制作用，在体内也表现出抗转移的作用。从机制上讲，GL-V9可促进AMPK的表达和活性，导致G6PD减少，p-ACC增加。因此，购买力平价水平受到抑制，而粮农组织的水平却大大提高。糖脂代谢的重新编程最终破坏了氧化还原平衡，导致细胞死亡。本文揭示了糖脂代谢参与氧化还原动态平衡调节的新机制，为TNBCs的抗转移治疗提供了一个潜在的候选靶点。在锚定独立生长中，FAO是ATP生成的主要途径，而不是糖酵解。从EMC分离的细胞中的葡萄糖被用于PPP，以抵抗OXPHOS形成的ROS。GL-V9通过破坏氧化还原动态平衡来抑制锚定非依赖性生长。AMPK是GL-V9诱导的糖脂代谢重编程的关键调节因子。
Breast cancer is one of the most lethal tumors in the world, among which 15% are triple-negative breast cancers (TNBCs) with higher metastasis and lower survival rate. Anoikis resistance is a key process during tumor metastasis, which is usually accompanied with metabolism reprogram. In this study, we established an anchorage independent growth model for MDA-MB-231 cells and investigated the changes in metabolism and redox homeostasis. Results showed that during detached-growth, MDA-MB-231 cells tend to generate ATP through fatty acid oxidation (FAO), instead of glycolysis. Amount of glucose was used for pentose phosphate pathway (PPP) to keep redox balance. Moreover, we discovered that a synthesized flavonoid derivative GL-V9, exhibited a potent inhibitory effect on the anchorage independent growth of TNBCs in vitro and anti-metastasis effect in vivo. In terms of the mechanism, GL-V9 could promote the expression and activity of AMPK, leading to the decrease of G6PD and the increase of p-ACC. Thus, the level of PPP was suppressed, whereas FAO was highly enhanced. The reprogram of glycolipid metabolism destroyed the redox balance ultimately and induced cell death. This paper indicated a novel regulating mechanism of redox homeostasis involving with glycolipid metabolism, and provided a potential candidate for the anti-metastatic therapy of TNBCs. Instead of glycolysis, FAO is the dominant way for ATP generation in anchorage independent growth. Glucose in cells detached from EMC is used for PPP to resist the ROS form OXPHOS. GL-V9 inhibits anchorage independent growth via imbalancing the redox homeostasis. AMPK is the critical regulator in GL-V9-induced glycolipid metabolism reprogram.
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影响因子：
5.3
作者：
Giannoni, E;Buricchi, F;Chiarugi, P
通讯作者：
Chiarugi, P
影响因子：
9
作者：
Ni T;He Z;Dai Y;Yao J;Guo Q;Wei L
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Wei L
影响因子：
5.9
作者：
Lee YM;Yoon Y;Yoon H;Park HM;Song S;Yeum KJ
通讯作者：
Yeum KJ
影响因子：
21.3
作者：
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影响因子：
5.3
作者：
Boerner, JL;Demory, ML;Parsons, SJ
通讯作者：
Parsons, SJ