Overaccumulation of p53-mediated autophagy protects against betulinic acid-induced apoptotic cell death in colorectal cancer cells.
Overaccumulation of p53-mediated autophagy protects against betulinic acid-induced apoptotic cell death in colorectal cancer cells.
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p53介导的自噬过度积累可防止结直肠癌细胞中桦木酸诱导的细胞凋亡
DOI：
10.1038/cddis.2017.485
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发表时间：
2017-10-05
影响因子：
9
通讯作者：
Bu Y
中科院分区：
文献类型：
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作者：
Wang S;Wang K;Zhang C;Zhang W;Xu Q;Wang Y;Zhang Y;Li Y;Zhang Y;Zhu H;Song F;Lei Y;Bu Y
白桦酸（BA）对某些癌细胞具有细胞毒活性。然而，BA对结直肠癌细胞的分子机制报道甚少。在这里，我们证明了BA以剂量依赖的方式诱导CRC细胞的生长抑制和凋亡。此外，BA处理通过抑制AKT-MTOR信号通路诱导自噬。自噬抑制剂氯喹或sirna介导的ATG5敲低对自噬的抑制可增强ba诱导的凋亡细胞死亡和抑制细胞增殖。此外，我们发现p53在wtp53和mutp53 CRC细胞中首先通过短时间暴露于BA激活，然后通过泛素介导的降解途径迅速降解。值得注意的是，BA在mutp53细胞（IC50值：HT29, 125 μM; SW480, 58 μM）中比在wtp53细胞（IC50值：HCT116, 178 μM）中表现出更优的细胞毒性。进一步的实验表明，sirna介导的p53敲低会减弱ba诱导的自噬，而强迫p53过表达会增强ba诱导的自噬，表明p53增强了ba诱导的自噬。此外，BA通过降解mutp53，增强了mutp53细胞对5-FU、ADR等化疗药物的敏感性。综上所述，我们的研究证明BA可以通过诱导细胞凋亡诱导结直肠癌细胞死亡，并通过降解依赖于泛素介导降解途径的wtp53和mutp53来减少BA诱导的保护性自噬的过度积累，达到杀伤作用，提示BA可能成为治疗mutp53癌症的一种新的理想药物。
Betulinic acid (BA) exhibits cytotoxic activity against some cancer cells. However, the molecular mechanism of BA against CRC cells was little reported. Here, we proved that BA elicited CRC cells' growth inhibition and apoptosis in a dose-dependent manner. In addition, BA treatment induced autophagy via inhibiting the AKT-MTOR signaling pathway. Inhibition of autophagy by either administration of autophagic inhibitor chloroquine or siRNA-mediated knockdown of ATG5 could augment BA-induced apoptotic cell death as well as inhibition of cell proliferation. Moreover, we found that p53 was firstly activated by short exposure to BA and then was rapidly degraded via the ubiquitin-mediated degradation pathway in both wtp53 and mutp53 CRC cells. Notably, more preferential cytotoxicity of BA was obtained in mutp53 cells (IC50 values: HT29, 125 μM; SW480, 58 μM) rather than wtp53 cells (IC50 values: HCT116, 178 μM). Further experiments demonstrated that siRNA-mediated p53 knockdown attenuated BA-induced autophagy, and forced overexpression of p53 augmented BA-induced autophagy, indicating that p53-enhanced BA-induced autophagy. Moreover, BA enhanced the sensitivity of mutp53 cells to chemotherapy drugs such as 5-FU and ADR by degradation of mutp53. Overall, our study proved that BA could induce CRC cell death by inducing apoptosis and reduce the overaccumulation of BA-induced protective autophagy by degrading wtp53 and mutp53 dependent on the ubiquitin-mediated degradation pathway to achieve killer effect, suggesting that BA might serve as a novel desirable drug for mutp53 cancer therapy.
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影响因子：
3.8
作者：
Chintharlapalli S;Papineni S;Lei P;Pathi S;Safe S
通讯作者：
Safe S
DOI：
10.1158/1940-6207.capr-10-0387
发表时间：
2011-07
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Chen HY;White E
通讯作者：
White E
MicroRNA-218 通过下调 BMI1 多梳环指癌基因抑制结肠癌细胞周期进程并促进细胞凋亡
影响因子：
5.7
作者：
He, Xinqi;Dong, Yujuan;Yu, Jun
通讯作者：
Yu, Jun
影响因子：
64.8
作者：
Green, Douglas R.;Kroemer, Guido
通讯作者：
Kroemer, Guido
影响因子：
9
作者：
通讯作者：
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