Targeting of lipid metabolism with a metabolic inhibitor cocktail eradicates peritoneal metastases in ovarian cancer cells
Targeting of lipid metabolism with a metabolic inhibitor cocktail eradicates peritoneal metastases in ovarian cancer cells
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DOI：
10.1038/s42003-019-0508-1
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发表时间：
2019-07-31
影响因子：
5.9
通讯作者：
Chan, David W.
中科院分区：
文献类型：
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作者：
Chen, Rain R.;Yung, Mingo M. H.;Chan, David W.
卵巢癌是一种腹内肿瘤，腹水的存在有助于转移扩散，并与预后不良有关。然而，卵巢癌细胞在腹水微环境中代谢变化的意义尚不清楚。在这里，我们显示卵巢癌细胞在腹水微环境中通过脂代谢的重新编程而表现出更强的侵袭性。在腹水微环境中培养的卵巢癌细胞具有较高的脂代谢活性，表明卵巢癌细胞的代谢从有氧糖酵解向β-氧化和脂肪生成转变。由于高能产生的反馈效应，AMP激活的蛋白激酶(AMPK)活性降低，导致其下游信号被激活，进而促进肿瘤生长。低毒的AMPK激活剂、转化生长因子β激活激酶1(TAK1)和脂肪酸合成酶(FASN)抑制剂的联合治疗可协同削弱卵巢癌的致癌增强作用。总体而言，靶向脂代谢信号轴阻碍卵巢癌腹膜转移。
Ovarian cancer is an intra-abdominal tumor in which the presence of ascites facilitates metastatic dissemination, and associated with poor prognosis. However, the significance of metabolic alterations in ovarian cancer cells in the ascites microenvironment remains unclear. Here we show ovarian cancer cells exhibited increased aggressiveness in ascites microenvironment via reprogramming of lipid metabolism. High lipid metabolic activities are found in ovarian cancer cells when cultured in the ascites microenvironment, indicating a metabolic shift from aerobic glycolysis to beta-oxidation and lipogenesis. The reduced AMP-activated protein kinase (AMPK) activity due to the feedback effect of high energy production led to the activation of its downstream signaling, which in turn, enhanced the cancer growth. The combined treatment of low toxic AMPK activators, the transforming growth factor beta-activated kinase 1 (TAK1) and fatty acid synthase (FASN) inhibitors synergistically impair oncogenic augmentation of ovarian cancer. Collectively, targeting lipid metabolism signaling axis impede ovarian cancer peritoneal metastases.