ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells.
ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells.
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DOI：
10.1038/s41419-017-0250-x
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Lo JF
中科院分区：
文献类型：
--
作者：
Chang CW;Chen YS;Tsay YG;Han CL;Chen YJ;Yang CC;Hung KF;Lin CH;Huang TY;Kao SY;Lee TC;Lo JF
肿瘤起始细胞(CICs)负责肿瘤的发生、发展和治疗耐药；此外，氧化还原动态平衡在调节肿瘤干细胞方面也很重要。在此之前，我们已经发现，含有低细胞内活性氧水平的癌细胞(ROSLow细胞)显示出CICs的增强特征。然而，CICs的特定代谢特征仍然不清楚，需要通过系统筛查来进一步表征。在这里，我们首先展示了CICs主要依赖于糖酵解，这对维持茎的特性是重要的。接下来，我们揭示了NRF2，抗氧化剂的主要调节者，即使在没有氧化应激的情况下，也能够维持CICs的低细胞内ROS水平。我们进一步鉴定了NRF2的激活是维持CICs特性所必需的。在ROSLow细胞中，NRF2的激活不仅直接激活糖酵解酶基因的转录，而且通过直接激活丙酮酸脱氢酶激酶1(PDK1)抑制三羧酸(TCA)循环，从而抑制丙酮酸向乙酰辅酶A的转化，从而促进Warburg效应。一个正调控的ROS非依赖性内质网应激途径(GRP78/p-PERK/NRF2信号)被确定为介导CICs的代谢转变(Warburg效应)和干性。最后，p-PERK和p-NRF2的共同表达与临床预后显著相关。我们的数据表明，NRF2在维持低ROS水平和CICs的干性相关特性方面起着中心节点的作用，这与临床结果显著相关，但不受ROS应激的影响。未来通过抑制NRF2激活的治疗可能在靶向CICs方面显示出巨大的潜力。
Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we have identified that cancer cells containing low intracellular reactive oxygen species levels (ROSLow cells) display enhanced features of CICs. However, the specific metabolic signatures of CICs remain unclear and are required for further characterization by systemic screenings. Herein, we first showed CICs mainly relying on glycolysis that was important for the maintenance of stemness properties. Next, we revealed that NRF2, a master regulator of antioxidants, was able to maintain low intracellular ROS levels of CICs, even though in the absence of oxidative stress. We further characterized that NRF2 activation was required for the maintenance of CICs properties. Of ROSLow cells, NRF2 activation not only directly activates the transcription of genes encoding glycolytic enzymes but also inhibited the conversion of pyruvate to acetyl-CoA by directly activating pyruvate dehydrogenase kinase 1 (PDK1) to lead to inhibition of tricarboxylic acid (TCA) cycle; therefore, to promote Warburg effect. A positive regulatory ROS-independent ER stress pathway (GRP78/p-PERK/NRF2 signaling) was identified to mediate the metabolic shift (Warburg effect) and stemness of CICs. Lastly, co-expression of p-PERK and p-NRF2 was significantly associated with the clinical outcome. Our data show that NRF2 acting as a central node in the maintenance of low ROS levels and stemness associated properties of the CICs, which is significantly associated with the clinical outcome, but independent from ROS stress. Future treatments by inhibiting NRF2 activation may exhibit great potential in targeting CICs.
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通讯作者：
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