Honokiol sensitizes breast cancer cells to TNF-alpha induction of apoptosis by inhibiting Nur77 expression
Honokiol sensitizes breast cancer cells to TNF-alpha induction of apoptosis by inhibiting Nur77 expression
复制标题
和厚朴酚通过抑制 Nur77 表达使乳腺癌细胞对 TNF-α 诱导细胞凋亡敏感
DOI：
10.1111/bph.13375
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发表时间：
2016
影响因子：
7.3
通讯作者：
Zhang Xiao-kun
中科院分区：
文献类型：
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作者：
Xie Lei;Jiang Fuquan;Zhang Xindao;Alitongbieke Gulimiran;Shi Xinlei;Meng MinJun;Xu Yiming;Ren Anshi;Wang Jing;Cai Lijun;Zhou Yunxia;Xu Yang;Su Ying;Liu Jie;Zeng Zhiping;Wang Guanghui;Zhou Hu;Chen Quan Cheng;Zhang Xiao-kun
背景与目的孤儿核受体Nur 77与肿瘤细胞的存活和凋亡有关。本研究的目的是确定Nur 77是否以及如何介导炎性细胞因子TNF-α在癌细胞中的作用，并确定和表征针对Nur 77的癌症治疗新药物。实验方法使用体外和体内模型研究TNF-α对Nur 77表达和功能的影响。在来自乳腺癌患者的肿瘤组织中评估Nur 77表达。TNF-α通过激活IκB激酶和JNK，快速、有效地诱导乳腺癌细胞Nur 77的表达，并通过体外、细胞和动物实验研究了TNF-α的抗肿瘤作用及其作用机制。敲低Nur 77导致TNF-α依赖性细胞凋亡，而MCF-7细胞中Nur 77的异位表达促进了它们在动物中的生长。在所研究的约50%的乳腺癌患者中，肿瘤组织中的Nur 77水平高于肿瘤周围的相应组织。我们的体外和动物实验也证实了和诺明是一种有效的肿瘤坏死因子-α诱导的细胞凋亡增敏剂，它通过抑制肿瘤坏死因子-α诱导的Nur 77 mRNA的表达，这可能是由于和诺明干预了肿瘤坏死因子受体1（TNFR 1）与受体相互作用蛋白1（RIPK 1）的相互作用。由于其已被证明的人体安全性，honoklastine代表了一种有前途的药物，值得进一步的临床开发。
Background and PurposeThe orphan nuclear receptor Nur77 is implicated in the survival and apoptosis of cancer cells. The purpose of this study was to determine whether and how Nur77 serves to mediate the effect of the inflammatory cytokine TNF‐α in cancer cells and to identify and characterize new agents targeting Nur77 for cancer therapy.Experimental ApproachThe effects of TNF‐α on the expression and function of Nur77 were studied usingin vitroandin vivomodels. Nur77 expression was evaluated in tumour tissues from breast cancer patients. The anticancer effects of honokiol and its mechanism of action were assessed byin vitro, cell‐based and animal studies.Key ResultsTNF‐α rapidly and potently induced the expression of Nur77 in breast cancer cells through activation of IκB kinase and JNK. Knocking down Nur77 resulted in TNF‐α‐dependent apoptosis, while ectopic Nur77 expression in MCF‐7 cells promoted their growth in animals. Levels of Nur77 were higher in tumour tissues than the corresponding tissues surrounding the tumour in about 50% breast cancer patients studied. Ourin vitroand animal studies also identified honokiol as an effective sensitizer of TNF‐α‐induced apoptosis by inhibiting TNF‐α‐induced Nur77 mRNA expression, which could be attributed to its interference of TNFR1's interaction with receptor‐interacting protein 1 (RIPK1).Conclusions and ImplicationsTNF‐α‐induced Nur77 serves as a survival factor to attenuate the death effect of TNF‐α in cancer cells. With its proven human safety profile, honokiol represents a promising agent that warrants further clinical development.