The putative oncotarget CSN5 controls a transcription-uncorrelated p53-mediated autophagy implicated in cancer cell survival under curcumin treatment.
The putative oncotarget CSN5 controls a transcription-uncorrelated p53-mediated autophagy implicated in cancer cell survival under curcumin treatment.
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DOI：
10.18632/oncotarget.11940
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Kong LD
中科院分区：
文献类型：
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作者：
Zhang QY;Jin R;Zhang X;Sheng JP;Yu F;Tan RX;Pan Y;Huang JJ;Kong LD
姜黄素已显示出作为安全和特异性抗癌剂的前景。COP 9信号体（CSN）组分CSN 5是姜黄素的已知特异性靶点，可以通过增加其通过泛素系统的降解来控制p53的稳定性。但CSN 5控制的p53与姜黄素的抗癌治疗作用的相关性目前尚不清楚。在这里，我们发现CSN 5控制的p53是转录失活的，并负责在姜黄素处理下的人类正常BJ细胞和癌症HepG 2细胞中的自噬。值得注意的是，姜黄素处理的CSN 5启动的细胞自噬在p53缺失的HCT 116 p53 −/−癌细胞中被消除，这可以通过用野生型p53或转录失活的p53突变体p53 R273 H重建来拯救。此外，CSN 5控制的p53在对姜黄素的不同癌细胞中赋予促存活自噬。基因p53缺失，以及自噬药理学抑制氯喹，显着增强姜黄素在体外和体内对癌细胞的治疗效果，但不是正常细胞。这项研究确定了一种新的CSN 5控制的p53在人类细胞的自噬。p53表达状态是预测姜黄素抗癌治疗效果的有用生物标志物。因此，药理学自噬操作可能有利于姜黄素正在进行的抗癌临床试验。
Curcumin has shown promise as a safe and specific anticancer agent. The COP9 signalosome (CSN) component CSN5, a known specific target for curcumin, can control p53 stability by increasing its degradation through ubiquitin system. But the correlation of CSN5-controlled p53 to anticancer therapeutic effect of curcumin is currently unknown. Here we showed that CSN5-controlled p53 was transcriptional inactive and responsible for autophagy in human normal BJ cells and cancer HepG2 cells under curcumin treatment. Of note, CSN5-initiated cellular autophagy by curcumin treatment was abolished in p53-null HCT116p53−/− cancer cells, which could be rescued by reconstitution with wild-type p53 or transcription inactive p53 mutant p53R273H. Furthermore, CSN5-controlled p53 conferred a pro-survival autophagy in diverse cancer cells response to curcumin. Genetic p53 deletion, as well as autophagy pharmacological inhibition by chloroquine, significantly enhanced the therapeutic effect of curcumin on cancer cells in vitro and in vivo, but not normal cells. This study identifies a novel CSN5-controlled p53 in autophagy of human cells. The p53 expression state is a useful biomarker for predicting the anticancer therapeutic effect of curcumin. Therefore, the pharmacologic autophagy manipulation may benefit the ongoing anticancer clinical trials of curcumin.