ISG12a and its interaction partner NR4A1 are involved in TRAIL-induced apoptosis in hepatoma cells
ISG12a and its interaction partner NR4A1 are involved in TRAIL-induced apoptosis in hepatoma cells
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ISG12a 及其相互作用伴侣 NR4A1 参与 TRAIL 诱导的肝癌细胞凋亡
DOI：
10.1111/jcmm.14251
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发表时间：
2019-05-01
影响因子：
5.3
通讯作者：
Zheng, Junnian
中科院分区：
文献类型：
--
作者：
Liu, Nianli;Wu, Zhiyuan;Zheng, Junnian
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可以诱导癌细胞凋亡而不影响正常细胞，从而导致开发用于癌症治疗的TRAIL受体激动剂。然而，由于缺乏生物标志物来预测患者是否对治疗有反应以及确定癌细胞对基于TRAIL的激动剂的抗性，这些基于激动剂的治疗剂几乎没有表现出临床益处。我们先前的研究已经证明ISG 12 a增强TRAIL诱导的细胞凋亡，并且可能作为预测TRAIL应答的生物标志物。ISG 12 a增强TRAIL诱导的细胞凋亡的下游机制仍有待阐明。在本研究中，我们发现ISG 12 a定位于线粒体和细胞核，并通过内源性凋亡途径增强TRAIL诱导的凋亡。此外，ISG 12 a与NR 4A 1相互作用并促进其核质易位。在易位到细胞质后，NR 4A 1靶向线粒体并诱导Bcl 2构象变化，从而暴露其BH 3结构域。此外，TRAIL处理可以通过激活TRAIL抗性Huh 7肝癌细胞中的NF-κ B来诱导NR 4A 1表达。NR 4A 1的敲低可以克服TRAIL抗性。然而，在TRAIL敏感的LH 86肝癌细胞中，TRAIL激活Jun N-末端激酶信号通路。总之，这些结果表明ISG 12 a及其相互作用伴侣NR 4A 1都参与了肝癌细胞中TRAIL介导的凋亡。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells while sparing normal cells, thereby leading to the development of TRAIL receptor agonists for cancer treatment. However, these agonist-based therapeutics exhibit little clinical benefits due to the lack of biomarkers to predict whether patients are responsive to the treatment, as well as determine the resistance of cancer cells to TRAIL-based agonists. Our previous study has demonstrated that ISG12a enhances TRAIL-induced apoptosis and might serve as a biomarker to predict the TRAIL response. The downstream mechanism by which ISG12a augments TRAIL-induced apoptosis remains to be elucidated. In this study, we found that ISG12a was localized in the mitochondria and nucleus and augmented TRAIL-induced apoptosis through intrinsic apoptotic pathway. In addition, ISG12a interacted with NR4A1 and promoted its nuclear-to-cytoplasm translocation. Upon translocate to cytoplasm, NR4A1 targeted mitochondria and induced Bcl2 conformational change, thereby exposing its BH3 domain. Moreover, TRAIL treatment can induce NR4A1 expression through the activation of NF-kappa B in TRAIL-resistant Huh7 hepatoma cells. Knockdown of NR4A1 could overcome TRAIL resistance. However, in TRAIL-sensitive LH86 liver cancer cells, TRAIL activated the Jun N-terminal kinases signalling pathway. Overall, these results showed that both ISG12a and its interaction partner NR4A1 are involved in TRAIL-mediated apoptosis in hepatoma cells.