Pheochromocytomas and paragangliomas (PCPGs) are catecholamine-producing neuroendocrine tumors. Accumulating evidences indicate that the blockade of antioxidative pathways might be a novel therapeutic approach to the treatment of PCPG. NIX has been confirmed to play a key role in maintaining redox homeostasis in tumors, while the function of NIX in PCPG remains unclear. In this study, the analyses of the disease-free survival (DFS) showed that high NIX protein level is related to poor prognosis in patients of PCPG. Consistent with this, high level of NIX protein upregulates the level of p-NF-κB and promotes the migration of PC12 cells. In NIX-over-expressing PC12 cells, the level of reactive oxygen species (ROS) is decreased while trolox-equivalent antioxidant capacity (TEAC) increased. But in NIX-silencing cells, ROS level is increased, while TEAC reversely reduced, consequently antioxidase and phase II enzymes of NRF2 signaling were activated, and elevated endoplasmic reticulum (ER) stress was observed. Additionally, the apoptosis induced by luminespib/NVP-AUY922, an inhibitor of heat shock protein 90 (HSP90, a cellular stress response factor), was enhanced in NIX-silencing cells but reduced in the NIX-over-expressing cells. All of these results indicated that high NIX protein level enhances antioxidant capacity of PC12 cells and reduces the apoptosis caused by cell stress, such as induced by luminespib/NVP-AUY922. Therefore, luminespib/NVP-AUY922 might be effective only for PCPG with low NIX level, while targeting NIX could be a further supplement to the therapeutic treatment strategy for PCPG patients with high NIX protein level.

嗜铬细胞瘤和副神经节瘤（PCPG）是产生儿茶酚胺的神经内分泌肿瘤。越来越多的证据表明，阻断抗氧化途径可能是治疗 PCPG 的一种新的治疗方法。NIX已被证实在维持肿瘤氧化还原稳态中发挥关键作用，但NIX在PCPG中的功能仍不清楚。在本研究中，无病生存（DFS）分析表明，高NIX蛋白水平与PCPG患者的不良预后相关。与此相一致的是，高水平的NIX蛋白上调p-NF-κB的水平并促进PC12细胞的迁移。在 NIX 过度表达的 PC12 细胞中，活性氧 (ROS) 水平降低，而 trolox 等效抗氧化能力 (TEAC) 增加。但在NIX沉默细胞中，ROS水平升高，而TEAC水平相反降低，从而激活NRF2信号传导的抗氧化酶和II相酶，并观察到内质网（ER）应激升高。此外，由 luminespib/NVP-AUY922（一种热休克蛋白 90（HSP90，一种细胞应激反应因子）抑制剂）诱导的细胞凋亡在 NIX 沉默细胞中增强，但在 NIX 过表达细胞中减少。所有这些结果表明，高NIX蛋白水平增强了PC12细胞的抗氧化能力，并减少了由细胞应激引起的细胞凋亡，例如由luminespib/NVP-AUY922诱导的细胞凋亡。因此，luminespib/NVP-AUY922可能仅对低NIX水平的PCPG有效，而靶向NIX可能是对高NIX蛋白水平PCPG患者治疗策略的进一步补充。