Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation
Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation
复制标题
核受体 Nur77 通过保护脂肪酸氧化促进代谢应激下黑色素瘤细胞的存活
DOI：
10.1016/j.molcel.2018.01.001
复制
发表时间：
2018-02-01
期刊：
影响因子：
16
通讯作者：
Chen, Hang-zi
中科院分区：
文献类型：
--
作者：
Li, Xiao-xue;Wang, Zhi-jing;Chen, Hang-zi
脂肪酸氧化（FAO）是细胞通过提供ATP和NADPH来克服代谢应激的关键。然而，FAO在肿瘤中调节的机制仍然难以捉摸。在这里，我们表明Nur 77是黑色素瘤细胞通过保护FAO进行代谢适应所必需的。葡萄糖剥夺激活ERK 2磷酸化并诱导Nur 77易位至线粒体，其中Nur 77与FAO中的限速酶TPb结合。虽然TPb活性通常在葡萄糖剥夺下被氧化抑制，但Nur 77-TPb缔合导致Nur 77自我牺牲以保护TPb免受氧化。因此，粮农组织能够维持NADPH和ATP水平，防止ROS增加和细胞死亡。Nur 77-TPb相互作用通过促进循环黑素瘤细胞存活进一步促进黑素瘤转移。这项研究证明了Nur 77在代谢应激期间与FAO-NADPH-ROS通路的连接的新的调节功能，表明Nur 77是黑色素瘤的潜在治疗靶点。
Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPb, a rate-limiting enzyme in FAO. Although TPb activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPb association results in Nur77 self-sacrifice to protect TPb from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPb interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.