State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, China.
Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
Mol Cell. 2018 Feb 1;69(3):480-492.e7. doi: 10.1016/j.molcel.2018.01.001. Epub 2018 Jan 27.
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 TPβ, a rate-limiting enzyme in FAO. Although TPβ activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPβ association results in Nur77 self-sacrifice to protect TPβ from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPβ 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.
脂肪酸氧化 (FAO) 对于细胞通过提供 ATP 和 NADPH 来克服代谢应激至关重要。然而，FAO 在肿瘤中的调节机制仍不清楚。在这里，我们表明 Nur77 通过保护 FAO 来促进黑色素瘤细胞的代谢适应。葡萄糖剥夺激活 ERK2 磷酸化并诱导 Nur77 向线粒体易位，在那里 Nur77 与 FAO 的限速酶 TPβ 结合。尽管在葡萄糖剥夺下氧化通常会抑制 TPβ 活性，但 Nur77-TPβ 结合导致 Nur77 自我牺牲以保护 TPβ 免受氧化。因此，FAO 能够维持 NADPH 和 ATP 水平，并防止 ROS 增加和细胞死亡。Nur77-TPβ 相互作用通过促进循环黑色素瘤细胞的存活进一步促进黑色素瘤转移。这项研究表明，在代谢应激过程中，Nur77 具有与 FAO-NADPH-ROS 途径相联系的新型调节功能，提示 Nur77 可能成为黑色素瘤的潜在治疗靶点。
