Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China.
Int J Biochem Cell Biol. 2013 Sep;45(9):2016-26. doi: 10.1016/j.biocel.2013.06.020. Epub 2013 Jul 3.
Autophagy is a cellular survival mechanism that involves the catabolic degradation of damaged proteins and organelles during stress. It is particularly required for tumor cell survival during starvation and tumorigenesis. NOR1 is a putative tumor suppressor gene. This study investigated in vitro the effects of NOR1 on the regulation of nasopharyngeal carcinoma autophagy, metabolism, and apoptosis. The data showed that acute oxidative stress induced the expression of NOR1 in normal human cells and tumor cells. Restoration of NOR1 expression downregulated basal autophagy, assessed by autophagy marker LC3 conversion and transmission electron microscopy. In NOR1-expressing tumor cells, reduced autophagy inhibited mitochondrial respiration and energy metabolism. Restoration of NOR1 expression in nasopharyngeal carcinoma cells enhanced apoptosis after induction of oxidative stress. NOR1 expression upregulated Bax expression, Bax translocation to the mitochondria, Smac/DIABLO release from the mitochondria, and activation of caspase-9, and -3, and PARP. In contrast, knockdown of NOR1 expression using NOR1 RNAi resulted in an increase in autophagy and attenuated hydrogen peroxide-induced cell death in HeLa cells. In addition, expression of NOR1 significantly inhibited cisplatin-induced autophagy, resulting in increased cisplatin cytotoxicity and apoptosis. These data revealed novel aspects of the interplay between autophagy and apoptosis in nasopharyngeal carcinoma cells, which underlies the tumor suppression function of NOR1. This work may provide novel insights to contribute to the development of a combinatorial therapy for nasopharyngeal carcinoma.
自噬是一种细胞生存机制，涉及到在应激时对受损蛋白质和细胞器的分解代谢降解。它在肿瘤细胞饥饿和肿瘤发生时的生存中特别需要。NOR1 是一种假定的肿瘤抑制基因。本研究探讨了 NOR1 在调节鼻咽癌细胞自噬、代谢和凋亡中的体外作用。研究数据表明，急性氧化应激诱导正常人类细胞和肿瘤细胞中 NOR1 的表达。通过自噬标志物 LC3 转化和透射电子显微镜评估，NOR1 表达的恢复下调了基础自噬。在 NOR1 表达的肿瘤细胞中，减少的自噬抑制了线粒体呼吸和能量代谢。在诱导氧化应激后，NOR1 表达的恢复增强了鼻咽癌细胞的凋亡。NOR1 表达上调了 Bax 的表达、Bax 向线粒体的易位、Smac/DIABLO 从线粒体的释放以及 caspase-9 和 -3 的激活和 PARP。相反，使用 NOR1 RNAi 敲低 NOR1 表达导致 HeLa 细胞中的自噬增加并减弱了过氧化氢诱导的细胞死亡。此外，NOR1 的表达显著抑制顺铂诱导的自噬，导致顺铂细胞毒性和凋亡增加。这些数据揭示了鼻咽癌细胞中自噬和凋亡相互作用的新方面，这是 NOR1 肿瘤抑制功能的基础。这项工作可能为鼻咽癌的联合治疗提供新的见解。
