Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers.
Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers.
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Magnolin 通过阻断人类结直肠癌中的 LIF/Stat3/Mcl-1 轴促进自噬和细胞周期停滞
DOI：
10.1038/s41419-018-0660-4
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发表时间：
2018-06-13
影响因子：
9
通讯作者：
Wang T
中科院分区：
文献类型：
--
作者：
Yu H;Yin S;Zhou S;Shao Y;Sun J;Pang X;Han L;Zhang Y;Gao X;Jin C;Qiu Y;Wang T
木兰脂素是一种具有多种生物活性的天然化合物，具有潜在的抗癌特性。然而，其机制仍有待阐明。在这里，我们报告木兰脂素在抑制人结直肠癌（CRC）细胞通过激活自噬和细胞周期阻滞在体外和体内的作用。用特异性自噬抑制剂（3-甲基腺嘌呤）预处理细胞或通过siRNA敲低内源性LC-3B显著消除木兰脂素诱导的细胞周期停滞。分子验证机制表明，木兰脂素诱导的自噬和细胞周期停滞在CRC细胞与白血病抑制因子（LIF）的转录水平降低，我们进一步发现，抑制LIF降低磷酸化水平的Stat 3和抑制转录表达的Mcl-1。此外，木兰脂素诱导的自噬和细胞周期阻滞抑制异种移植结直肠肿瘤的生长，而没有明显的毒性。最后，我们评估了大肠癌患者组织中LIF/Stat 3/Mcl-1的临床相关性。正如预期的那样，LIF、p-Stat 3和Mcl-1水平在CRC组织中很高，但在正常结肠组织中几乎没有发现。LIF或Mcl-1高阳性表达者预后差。双重阳性的病例显示出最坏的结果。综上所述，我们的研究结果阐明了木兰脂素通过LIF/Stat 3/Mcl-1途径诱导CRCs自噬和细胞周期阻滞的新分子机制。我们的研究结果还表明，木兰脂素在CRC中具有很好的治疗潜力。
Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.
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影响因子：
29
作者：
Kimmelman AC;White E
通讯作者：
White E
SQSTM1/p62的上调有助于镍诱导的人支气管上皮细胞的恶性转化
影响因子：
13.3
作者：
Huang H;Zhu J;Li Y;Zhang L;Gu J;Xie Q;Jin H;Che X;Li J;Huang C;Chen LC;Lyu J;Gao J;Huang C
通讯作者：
Huang C
影响因子：
15.9
作者：
Liu, Shu-Chen;Tsang, Ngan-Ming;Chang, Yu-Sun
通讯作者：
Chang, Yu-Sun
影响因子：
--
作者：
Li X;Yang Q;Yu H;Wu L;Zhao Y;Zhang C;Yue X;Liu Z;Wu H;Haffty BG;Feng Z;Hu W
通讯作者：
Hu W
Gartanin 诱导细胞周期停滞和自噬，并抑制人胶质瘤细胞中涉及 PI3K/Akt/mTOR 和 MAPK 信号通路的迁移
影响因子：
5.3
作者：
Luo M;Liu Q;He M;Yu Z;Pi R;Li M;Yang X;Wang S;Liu A
通讯作者：
Liu A