Induction of Nur77-dependent apoptotic pathway by a coumarin derivative through activation of JNK and p38 MAPK
Induction of Nur77-dependent apoptotic pathway by a coumarin derivative through activation of JNK and p38 MAPK
复制标题
香豆素衍生物通过激活 JNK 和 p38 MAPK 诱导 Nur77 依赖性细胞凋亡途径
DOI：
10.1093/carcin/bgu186
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发表时间：
2014-12-01
期刊：
影响因子：
4.7
通讯作者：
Zhang, Xiao-Kun
中科院分区：
文献类型：
--
作者：
Zhou, Yuqi;Zhao, Wei;Zhang, Xiao-Kun
香豆素类化合物是植物源性天然产物，具有广泛的药理活性，包括抗癌作用。然而，这类有前途的化合物发挥其抗癌作用的分子机制在很大程度上仍然未知。本文报道了一种名为apaensin的呋喃香豆素能通过激活JNK和p38丝裂原活化蛋白激酶（MAPK）有效地诱导肿瘤细胞凋亡。JNK和p38 MAPK的化学抑制剂可抑制apaensin诱导的癌细胞凋亡。通过小干扰RNA（siRNA）方法抑制孤儿核受体Nur 77的表达也消除了apaensin的死亡效应。分子分析表明，JNK激活所需的Nur 77，一个已知的癌细胞凋亡事件的核输出。虽然p38 MAPK激活不参与Nur 77核输出，但它通过诱导Nur 77与Bcl-2的相互作用而对Nur 77线粒体靶向至关重要，这也已知将Bcl-2从抗凋亡分子转化为促凋亡分子。总之，我们的研究结果确定了一种新的天然产物，通过其独特的JNK和p38 MAPK激活作用靶向孤儿核受体Nur 77，并为Nur 77-Bcl-2凋亡途径的复杂调控提供了见解。
Coumarins are plant-derived natural products with a broad range of known pharmacological activities including anticancer effects. However, the molecular mechanisms by which this class of promising compounds exerts their anticancer effects remain largely unknown. We report here that a furanocoumarin named apaensin could effectively induce apoptosis of cancer cells through its activation of Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Apoptosis induction by apaensin in cancer cells was suppressed by chemical inhibitors of JNK and p38 MAPK. Inhibition of the expression of orphan nuclear receptor Nur77 by small interfering RNA (siRNA) approach also abrogated the death effect of apaensin. Molecular analysis demonstrated that JNK activation was required for the nuclear export of Nur77, a known apoptotic event in cancer cells. Although p38 MAPK activation was not involved in Nur77 nuclear export, it was essential for Nur77 mitochondrial targeting through induction of Nur77 interaction with Bcl-2, which is also known to convert Bcl-2 from an antiapoptotic to a proapoptotic molecule. Together, our results identify a new natural product that targets orphan nuclear receptor Nur77 through its unique activation of JNK and p38 MAPK and provide insight into the complex regulation of the Nur77-Bcl-2 apoptotic pathway.