Department of Clinical laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Int J Med Sci. 2018 Apr 3;15(7):674-681. doi: 10.7150/ijms.23782. eCollection 2018.
The cullin-RING ligase (CRL)-NEDD8 pathway maintains essential cellular processes, including cell cycle progression, apoptosis, autophagy, DNA repair, antigen processing and signal transduction. Growing evidence demonstrates that the alteration of the CRL-NEDD8 pathway in some cancers constitutes an attractive target for therapeutic intervention, but the roles of CRL-NEDD8 pathway in acute promyelocytic leukemia (APL) is still unclear. In the present study, we found that ATRA could decrease the expression of NEDD8-activating enzyme E1 (NAE1) and inhibit the neddylation of cullin1 and cullin3 in the APL cell line NB4. Inactivation of cullin neddylation promoted self-degradation of F-box proteins (Skp2, KLHL20, βTrCP) and up-regulated the protein expression of p27, DEPTOR and DAPK1. MLN4924, a novel inhibitor of NAE1, significantly suppressed cell growth and enhanced apoptosis of APL cells by blocking cullin neddylation and subsequent accumulation of CRL E3 substrates. Furthermore, MLN4924 effectively enhanced ATRA-induced differentiation of APL cells by promoting autophagy. Our findings not only provide further insights into the mechanism of the CRL-NEDD8 axis, but also provide a better understanding of this pathway as a potential target for therapeutic intervention in APL.
Cullin-RING 连接酶 (CRL)-NEDD8 通路维持着重要的细胞过程，包括细胞周期进程、细胞凋亡、自噬、DNA 修复、抗原处理和信号转导。越来越多的证据表明，某些癌症中 CRL-NEDD8 通路的改变构成了治疗干预的有吸引力的靶点，但 CRL-NEDD8 通路在急性早幼粒细胞白血病 (APL) 中的作用仍不清楚。在本研究中，我们发现 ATRA 可以降低 NEDD8 激活酶 E1 (NAE1) 的表达，并抑制 APL 细胞系 NB4 中 cullin1 和 cullin3 的 neddylation。cullin 去 neddylation 的失活促进了 F-box 蛋白（Skp2、KLHL20、βTrCP）的自我降解，并上调了 p27、DEPTOR 和 DAPK1 的蛋白表达。NAE1 的新型抑制剂 MLN4924 通过阻断 cullin neddylation 和随后 CRL E3 底物的积累，显著抑制 APL 细胞的生长并增强细胞凋亡。此外，MLN4924 通过促进自噬有效地增强了 ATRA 诱导的 APL 细胞分化。我们的研究结果不仅进一步深入了解了 CRL-NEDD8 轴的机制，还更好地理解了该通路作为 APL 治疗干预的潜在靶点。
