Aurora A激酶抑制剂Alisertib诱导结直肠癌细胞自噬的作用及与p53表达间的关系

doi:10.3969/j.issn.1009-976X.2021.01.014

岭南现代临床外科 ›› 2021, Vol. 21 ›› Issue (01): 82-86.DOI: 10.3969/j.issn.1009-976X.2021.01.014

Aurora A激酶抑制剂Alisertib诱导结直肠癌细胞自噬的作用及与p53表达间的关系

任宝军¹, 剧永乐¹, 封静¹, 陈淑香², 刘家旋¹, 罗振涛¹, 王家智¹, 杨帆¹, 李德智¹, 董博业¹, 耿岩^1,*

1.南方医科大学顺德医院（佛山市顺德区第一人民医院）胃肠外科,广东顺德 528308;
2.南方医科大学顺德医院（佛山市顺德区第一人民医院）麻醉手术室,广州 528308

通讯作者: *耿岩,E-mail：gengyan666@163.com
基金资助:
广东省医学科学技术研究基金（A2018150）; 佛山市医学类科技攻关项目（2017AB003533）; 南方医科大学顺德医院科研启动计划项目（SRSP2018002）; 佛山市医学骨干人才项目（耿岩）

Alisertib, an Aurora a Kinase inhibitor, induces autophagy of colorectal cancer cells and its relationship with p53 expression

REN Bao-jun¹, JU Yong-le¹, FENG Jing¹, CHEN Shu-xiang², LIU Jia-xuan¹, LUO Zhen-tao¹, WANG Jia-zhi¹, YANG Fan¹, LI De-zhi¹, DONG Bo-ye, GENG Yan¹

1. Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Shunde （The First People′s Hospital of Shunde）, Guangdong 528308, China;
2. Department of Anesthesia, Shunde Hospital, Southern Medical University （The First People′s Hospital of Shunde）, Shunde, Guangdong 528308, China

Received:2020-08-16 Online:2021-02-20 Published:2021-04-08
Contact: GENG Yan, gengyan666@163.com

摘要/Abstract

摘要： 目的探讨Alisertib（ALS）对人结直肠癌Caco-2和HT29细胞的诱导自噬的作用及与p53 表达状态间的关系。方法本研究采用人结直肠癌Caco-2和HT29细胞进行实验。实验组用0.1、1、5 μmol/L ALS而对照组用同浓度的DMSO处理细胞。流式细胞术检测细胞的自噬率,Wester Blotting法检测细胞自噬过程中关键调节分子的蛋白表达。结果与对照组比较,0.1、1 μmol/L Alisertib组Caco-2细胞自噬率增加,分别为26.4%和26.8%（P<0.01）。1、5 μmol/L ALS组HT29细胞自噬率增加,分别为36.8%和42.6%（P<0.01）。Caco-2细胞不表达p53蛋白,而HT29细胞表达p53蛋白。与对照组比较,1、5μmol/L Alisertib引起Caco-2细胞的p-PI3K/PI3K、p-Akt/Akt和p-p38/p38的比值分别降低为对照组的62.6%、45.2%,30.1%、38.2%和49.0%、30.4%（P<0.01）,LC3-Ⅱ/LC3-I的比值升高32.6%、46.8%（P<0.01）。与对照组比较,1、5 μmol/L Alisertib引起HT29细胞的p-PI3K/PI3K、p-Akt/Akt的比值分别降低为对照组的70.9%、66.3%和85.2%、27.2%（P<0.01）,p-p38/p38和LC3-II/LC3-I的比值升高2.1倍、2.0倍和78.5%、84.8%（P<0.05）。与5 μmol/L Alisertib组比较,10 μmol/L SB202190+5 μmol/L Alisertib引起HT29细胞凋亡率升高64.7%（P<0.001）,而Caco-2细胞凋亡率无明显变化。结论 Alisertib抑制了PI3K/Akt信号通路,诱导了Caco-2和HT29细胞发生细胞自噬。Alisertib对p38 MAPK信号通路的影响不同,激活了HT29而抑制了Caco-2细胞的p38 MAPK信号通路,可能与p53蛋白是否表达有关。

关键词: Alisertib, Aurora A, p53, 结直肠癌, 自噬

Abstract: Objective To explore the effect of Alisertib （ALS） on human colorectal cancer Caco-2 and HT29 cells in inducing autophagy and its relationship with the expression of p53. Methods In this study, human colorectal cancer Caco-2 and HT29 cells were used for experiments. The experimental groups were treated with 0.1, 1, and 5 μmol/L ALS and the control group was treated with the same concentration of DMSO. The autophagy rate of cells was detected by flow cytometry. The protein expression levels of key regulatory molecules in the process of cell autophagy were examined by wester blotting. Results Compared with the control group, the autophagy rate of Caco-2 cells in the 0.1 and 1 μmol/L Alisertib groups increased to 26.4% and 26.8% （P<0.01）. The autophagy rate of HT29 cells in the 1 and 5 μmol/L ALS groups increased to 36.8% and 42.6% （P<0.01）. Caco-2 cells did not express p53 protein, while HT29 cells expressed p53 protein. Compared with the control group, the ratio of p-PI3K/PI3K, p-Akt/Akt and p-p38/p38 in Caco-2 cells after treatment with 1, 5 μmol/L alisertib decreased to 62.6%, 45.2%, 30.1%, 38.2% and 49.0%, 30.4% （P<0.01）, while the ratio of LC3-II/LC3-I increased by 32.6%, 46.8% （P<0.01）. 1, 5 μmol/L Alisertib caused the p-PI3K/PI3K and p-Akt/Akt ratios of HT29 cells to decrease to 70.9%, 66.3% and 85.2%, 27.2% （P<0.01）, while the ratio of p38/p38 and LC3-Ⅱ/LC3-I increased by 2.1 times, 2.0 times and 78.5%, 84.8% （P<0.05）. Compared with the 5 μmol/L Alisertib group, 10 μmol/L SB202190+5 μmol/L Alisertib increased the apoptotic rate of HT29 cells by 64.7% （P<0.001）, while the apoptotic rate of Caco-2 cells did not change significantly. Conclusion Alisertib induces autophagy in Caco-2 and HT29 cells by inhibiting PI3K/Akt signaling pathway. Alisertib activates the p38 MAPK signaling pathway in HT29 but inhibits the p38 MAPK signaling pathway in Caco-2 cells, which may be related to the expresion of p53 protein.

Key words: Alisertib, Aurora A, p53, colorectal cancer, autophagy

中图分类号:

任宝军, 剧永乐, 封静, 陈淑香, 刘家旋, 罗振涛, 王家智, 杨帆, 李德智, 董博业, 耿岩. Aurora A激酶抑制剂Alisertib诱导结直肠癌细胞自噬的作用及与p53表达间的关系[J]. 岭南现代临床外科, 2021, 21(01): 82-86.

REN Bao-jun, JU Yong-le, FENG Jing, CHEN Shu-xiang, LIU Jia-xuan, LUO Zhen-tao, WANG Jia-zhi, YANG Fan, LI De-zhi, DONG Bo-ye, GENG Yan. Alisertib, an Aurora a Kinase inhibitor, induces autophagy of colorectal cancer cells and its relationship with p53 expression[J]. Lingnan Modern Clinics In Surgery, 2021, 21(01): 82-86.

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Aurora A激酶抑制剂Alisertib诱导结直肠癌细胞自噬的作用及与p53表达间的关系

Alisertib, an Aurora a Kinase inhibitor, induces autophagy of colorectal cancer cells and its relationship with p53 expression

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