Celastrol inhibits PAK1 kinase and inhibits the proliferation of pancreatic cancer cells
Celastrol inhibits PAK1 kinase and inhibits the proliferation of pancreatic cancer cells
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DOI：
10.16438/j.0513-4870.2019-0580
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发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Cao Peng
中科院分区：
文献类型：
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作者：
Zhu Ling-xia;Sun Xiao-yan;Cao Peng
p21 激活激酶 1 (PAK1) 是 P21 激活蛋白激酶家族的成员，在胰腺癌的增殖和同生中发挥重要作用。 PAK1是治疗胰腺癌的重要靶点。目前，针对PAK1的激酶抑制剂仍处于临床前研究阶段。因此，筛选新型PAK1激酶抑制剂具有重要意义。本研究发现天然化合物雷公藤红醇对PAK1具有显着的抑制作用，IC50值为3.614 mu mol.L-1。分子对接结果表明雷公藤红素与PAK1有良好的结合。 MTT实验表明雷公藤红醇抑制胰腺癌细胞BxPC-3和PANC-1的增殖。机制研究表明，雷公藤红素对胰腺癌细胞的抑制作用可被 PAK1 siRNA 逆转。雷公藤红素抑制PAK1及随后下游信号通路的激活，从而激活凋亡信号通路并引发胰腺癌细胞凋亡。这些发现表明雷公藤红素通过抑制PAK1激酶信号通路诱导胰腺癌细胞凋亡，具有潜在的治疗胰腺癌的价值。
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 mu mol.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.