Dual PPAR?/? agonist oroxyloside suppresses cell cycle progression by glycolipid metabolism switch-mediated increase of reactive oxygen species levels
Dual PPAR?/? agonist oroxyloside suppresses cell cycle progression by glycolipid metabolism switch-mediated increase of reactive oxygen species levels
复制标题
双 PPARγ/É 激动剂 oroxyloside 通过糖脂代谢开关介导的活性氧水平增加抑制细胞周期进程
DOI：
10.1016/j.freeradbiomed.2021.02.032
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发表时间：
2021-03-21
影响因子：
7.4
通讯作者：
Wei，Libin
中科院分区：
文献类型：
--
作者：
Zhou，Yuxin;Guo，Yongjian;Wei，Libin
癌细胞更喜欢依赖有氧糖酵解而不是丙酮酸氧化来满足快速增殖的高能量需求。过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPARs）是一类重要的配体诱导型转录因子，在糖脂代谢中起重要作用。仔细设计PPARs的新型激动剂可以显示副作用的改善，并且还增加对癌症和其他代谢紊乱疾病的治疗价值。与正常人肝细胞相比，肝细胞癌（HCC）中PPARs的表达或活性较低。本研究表明，木菠萝苷（oroxyloside，OAG）是一种新型的PPARγ/PPAR γ双重激动剂，通过代谢开关抑制肝癌细胞增殖。OAG通过对糖脂代谢酶的依赖性和非依赖性调节，关闭葡萄糖的催化作用，促进脂肪酸氧化生成乙酰辅酶A，用于TCA循环和氧化磷酸化。OAG诱导的代谢开关导致活性氧（ROS）水平显著增加，导致RB快速去磷酸化和细胞周期停滞在G1期。丙酮酸脱氢酶激酶4（PDK 4）和β-氧化是OAG抑制细胞周期进程所必需的。总之，我们的研究结果提供了一种新的候选药物和一种基于代谢重编程的肝细胞癌可行的治疗策略。
Cancer cells prefers to rely on aerobic glycolysis than pyruvate oxidation to meet the high demand of energy for rapidly proliferation. Peroxisome proliferator-activated receptors (PPARs) are a kind of important ligand-inducible transcription factors and play crucial roles in glucose and lipid metabolism. Careful designing of novel agonists for PPARs, may show improvement with the side effects and also increase the therapeutic value for cancer and other metabolic disorder diseases. Compared with normal human liver cells, lower expression or acitivity of PPARs is observed in hepatocellular carcinoma (HCC). In this study, we show that oroxyloside (OAG) is a new dual agonist of PPARγ/ɑ, and inhibits cell proliferation of HCC based on metabolic switch. Via both PPAR-dependent and PPAR-independent regulations on glycolipid metabolic enzymes, OAG shuts down the catabolism of glucose and promotes fatty acids oxidation to generate acetyl-CoA for TCA cycle and oxidative phosphorylation. The metabolic switch induced by OAG results in a marked increase of reactive oxygen species (ROS) levels, leading to rapid dephosphorylation of RB and cell-cycle arrest in G1 phase. Pyruvate dehydrogenase kinase 4 (PDK4) and β-Oxidation are required for the suppression of cell cycle progression by OAG. Together, our findings provide a new drug candidate and a viable therapeutic strategy for HCC based on metabolic reprogram.