Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis
Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis
复制标题
孤儿受体TR3通过Chk2磷酸化参与顺铂诱导的细胞凋亡以抑制肠道肿瘤发生
DOI：
10.1093/carcin/bgr287
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发表时间：
2012-02-01
期刊：
影响因子：
4.7
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Yao, Lu-ming;He, Jian-ping;Wu, Qiao
顺铂是一种广泛使用的抗肿瘤药物，其通过触发参与凋亡的细胞蛋白来诱导侵袭性癌细胞死亡。在这里，我们证明，顺铂有效地诱导孤儿核受体TR 3磷酸化通过激活Chk 2激酶活性，促进这两种蛋白质之间的串扰，从而有助于通过细胞凋亡抑制肠道肿瘤的发生。机制分析表明，Chk 2诱导的磷酸化使TR 3能够与BRE和RNF-7基因启动子上的反应元件结合，导致这两个抗凋亡基因的负调控。此外，顺铂诱导的细胞凋亡是由TR 3介导的，TR 3的敲低使结肠癌细胞中顺铂诱导的细胞凋亡减少27%。TR 3在顺铂化疗中的作用在小鼠模型中进一步阐明。在Apc（min/+）小鼠中，顺铂以TR 3磷酸化依赖性方式抑制70%的肠道肿瘤发生;然而，Apc（min/+）/TR 3（-/-）小鼠中TR 3功能的丧失导致顺铂诱导的肿瘤发生抑制失败。一致地，源自TR 3敲低的结肠癌细胞的异种移植物对顺铂治疗不敏感，而在具有功能性TR 3的异种移植物中观察到显著的疗效（50%抑制）。综上所述，我们的研究揭示了Chk 2和TR 3之间的一种新的串扰，并揭示了顺铂通过TR 3诱导细胞凋亡的机制。因此，TR 3可能成为顺铂治疗结肠癌的新靶点。
Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross talk between these two proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic analysis has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the negative regulation of these two anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knockdown of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy is further clarified in mouse models. In Apc(min/+) mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apc(min/+)/TR3(-/-) mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knockdown colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is observed in xenografts with functional TR3. Taken together, our study reveals a novel cross talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy.