Usenamine A通过下调PLK1激活自噬抑制人肝癌细胞生长  

Usenamine A inhibits the growth of human hepatocellular carcinoma cells by activating autophagy through down-regulation of PLK1

作　　者：魏雪娇 杨爱琳[1,2] 刘东晓 蔡依林 黄惠铭 王飞 王柱国 胡仲冬 WEI Xue-jiao;YANG Ai-lin;LIU Dong-xiao;CAI Yi-lin;HUANG Hui-ming;WANG Fei;WANG Zhu-guo;HU Zhong-dong(School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 100029,China;Modern Research Center for Traditional Chinese Medicine,Beijing Institute of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]北京中医药大学中药学院,北京100029 [2]北京中医药大学,北京中医药研究院,中药现代研究中心,北京100029

出　　处：《药学学报》2025年第3期587-594,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81873044);北京中医药大学国家级人才精准培育计划(JZPY202206);中央高校基本科研业务费专项资金(2023-JYB-JBQN-051)。

摘　　要：松萝胺A(usenamine A,UA)为本课题组从中药长松萝中分离得到的一个二苯并呋喃类化合物,前期研究显示UA具有良好的体内外抗肝癌活性,且其能够诱导人肝癌细胞凋亡和自噬,本研究对其抗肝癌分子作用机制进行了进一步探究。基于前期基因芯片检测数据提示以及实时荧光定量PCR和免疫印迹法结果显示,UA能够抑制人肝癌HepG2和SK-HEP-1细胞中polo样激酶1(polo-like kinase 1,PLK1)的表达。PLK1抑制剂BI 6727给药能够显著削弱UA对人肝癌细胞活力的抑制作用。利用RNA干扰技术敲低PLK1的表达能够显著抑制人肝癌细胞的增殖能力,而且敲低PLK1能够削弱UA对人肝癌细胞活力的抑制作用。此外,敲低PLK1表达能够明显上调人肝癌细胞的凋亡率,而且可以显著削弱UA对人肝癌细胞的凋亡诱导作用。借助自噬抑制剂3-MA抑制自噬能够削弱UA对人肝癌细胞的增殖抑制作用。借助PLK1抑制剂BI 6727或RNA干扰技术,本课题组还发现在人肝癌细胞中PLK1能够负向调节自噬,而且抑制PLK1能够削弱UA对人肝癌细胞自噬的诱导作用。因此,PLK1在UA抑制人肝癌细胞增殖和诱导凋亡中发挥了重要作用,而且UA能够通过抑制PLK1激活自噬,进而发挥抑制人肝癌细胞生长的作用。Usenamine A(UA)is a dibenzofuran compound isolated from Usnea longissima Arch.Previous studies have demonstrated that UA exhibited significant in vitro and in vivo anti-hepatocellular carcinoma activity,inducing both apoptosis and autophagy in human hepatocellular carcinoma cells.This study aims to further elucidate the molecular mechanism underlying its anti-hepatocellular carcinoma effect.Based on data obtained from gene chip assay,real-time quantitative PCR,and Western blot analysis,we found that UA effectively inhibited the expression of polo-like kinase 1(PLK1)in human hepatocellular carcinoma HepG2 and SK-HEP-1 cells.Furthermore,the administration of BI 6727,a PLK1 inhibitor,significantly diminished the inhibitory effect of UA on the viability of human hepatocellular carcinoma cells.Additionally,the knockdown of PLK1 expression via RNA interference markedly inhibited the proliferation of human hepatocellular carcinoma cells,and the inhibitory effect of UA on cell viability was attenuated upon PLK1 knockdown.The knockdown of PLK1 expression significantly upregulated the apoptosis rate of human hepatocellular carcinoma cells and notably diminished the apoptosis-inducing effect of UA on these cells.Additionally,the inhibition of autophagy using the autophagy inhibitor 3-MA reduced the proliferation-inhibitory effect of UA on human hepatocellular carcinoma cells.Utilizing the PLK1 inhibitor BI 6727 or RNA interference,we further demonstrated that PLK1 negatively regulated autophagy in human hepatocellular carcinoma cells.Consequently,the inhibition of PLK1 attenuated the autophagy induction by UA on these cells.Thus,PLK1 plays a crucial role in the inhibition of human hepatocellular carcinoma cell proliferation and the induction of apoptosis by UA.Moreover,UA activates autophagy through the inhibition of PLK1,which subsequently exerts an inhibitory effect on the growth of human hepatocellular carcinoma cells.

关 键 词：松萝胺A 肝癌 POLO样激酶1 增殖 自噬 凋亡 

分 类 号：R966[医药卫生—药理学]