药学学报, 2020, 55(1): 60-66
引用本文:
朱陵霞, 孙晓艳, 陈姣, 蔡雪婷, 曹鹏. 雷公藤红素通过抑制PAK1抗胰腺癌作用及其机制研究[J]. 药学学报, 2020, 55(1): 60-66.
ZHU Ling-xia, SUN Xiao-yan, CHEN Jiao, CAI Xue-ting, CAO Peng. Celastrol inhibits PAK1 kinase and inhibits the proliferation of pancreatic cancer cells[J]. Acta Pharmaceutica Sinica, 2020, 55(1): 60-66.

雷公藤红素通过抑制PAK1抗胰腺癌作用及其机制研究
朱陵霞1,2, 孙晓艳1,2, 陈姣1,2, 蔡雪婷1,2, 曹鹏1,2
1. 南京中医药大学附属中西医结合医院, 江苏 南京 210028, 江苏 南京 210023;
2. 南京中医药大学药学院, 江苏 南京 210023
摘要:
P21活化蛋白激酶1(p21-activated kinases 1,PAK1)是P21活化蛋白激酶家族成员之一,在胰腺癌细胞增殖和肿瘤形成过程中起着十分重要的作用,是胰腺癌治疗的重要靶点。目前,靶向PAK1的激酶抑制剂尚处于临床前研究阶段。因此,筛选开发出新的PAK1激酶抑制剂对于胰腺癌治疗具有重要的意义。本研究发现天然产物雷公藤红素(celastrol)对PAK1具有显著的抑制作用,其IC50约为3.614 μmol·L-1。分子对接结果显示,雷公藤红素与PAK1激酶结构域的ATP结合口袋结合。MTT实验结果表明,雷公藤红素对胰腺癌细胞BxPC-3、PANC-1的增殖均具有抑制作用。进一步机制研究显示,干扰PAK1后,雷公藤红素对胰腺癌细胞BxPC-3的抑制作用发生逆转。同时,雷公藤红素可以抑制PAK1及其下游信号通路蛋白的表达,从而激活凋亡信号通路引发胰腺癌细胞发生凋亡。上述研究结果表明,雷公藤红素可以通过靶向抑制PAK1激酶信号通路诱导胰腺癌细胞的凋亡,具有用于治疗胰腺癌的潜在价值。
关键词:    P21活化蛋白激酶1      胰腺癌      雷公藤红素      增殖      凋亡     
Celastrol inhibits PAK1 kinase and inhibits the proliferation of pancreatic cancer cells
ZHU Ling-xia1,2, SUN Xiao-yan1,2, CHEN Jiao1,2, CAI Xue-ting1,2, CAO Peng1,2
1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing 210028, China, Nanjing University of Chinese Medicine, Nanjing 210023, China;
2. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
Abstract:
The p21-activated kinase 1 (PAK1) is a member of the P21-activated protein kinase family that plays an important role in the proliferation and on cogenesis of pancreatic cancer. PAK1 is an important target for the treatment of pancreatic cancer. At present, akinase inhibitor targeting PAK1 is still in the preclinical research stage. Therefore, screening for new PAK1 kinase inhibitors is of great significance. In this study the natural compound celastrol was found to have a significant inhibitory effect on PAK1, with an IC50 value of 3.614 μmol·L-1. Molecular docking results showed that celastrol had good binding to PAK1. An MTT assay indicated that celastrol inhibited the proliferation of pancreatic cancer cells BxPC-3 and PANC-1. Mechanistic studies revealed that the inhibition of pancreatic cancer cells by celastrol was reversed by PAK1 siRNA. Celastrol inhibited PAK1 and the subsequent activation of downstream signaling pathways, thereby activating apoptosis signaling pathways and triggering apoptosis in pancreatic cancer cells. These findings suggested that celastrol induced apoptosis in pancreatic cancer cells by suppressing the PAK1 kinase signaling pathway and has potential value for the treatment of pancreatic cancer.
Key words:    p21-activated kinase 1    pancreatic neoplasms    tripterine    proliferation    apoptosis   
收稿日期: 2019-07-19
DOI: 10.16438/j.0513-4870.2019-0580
基金项目: 国家自然科学基金资助项目(81873057,81973527);江苏省社会发展——临床前沿技术项目(BE2018755).
通讯作者: 曹鹏,Tel:86-25-85608666,E-mail:cao_peng@njucm.edu.cn
Email: cao_peng@njucm.edu.cn
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