Oridonin induces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLa cell line  

作　　者：Hong-zhen HU Yue-bo YANG Xiang-dong XU Hong-wei SHEN Yi-min SHU Zi REN Xiao-mao LI Hui-ming SHEN Hai-tao ZENG 

机构地区：[1]Department of Gynecology and Obstetrics, Yijishan Hospital, Wannan Medical College, Wuhu 241001, China [2]Department of Gynecology and Obstetrics, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China [3]Department of Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China [4]Department of Gynecology and Obstetrics, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China [5]Department of Obstetrics and Gynecology, IVF Program, Stanford University Medical Center, Palo Alto, CA 94304, USA [6]Department of Gynecology and Obstetrics, Guangdong Provincial People's Hospital, Guangzhou510080, China

出　　处：《Acta Pharmacologica Sinica》2007年第11期1819-1826,共8页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(№ 30571956);the Medical Science and Technology Research Fund of Guangdong Province(№ A2006188)

摘　　要：Aim： To investigate the apoptosis-inducing effect of oridonin, a diterpenoid isolated from Rabdosia rubescens, in the human cervical carcinoma HeLa cell line. Methods： A morphological analysis, nuclear condensation, and fragmentation of chromatin were monitored using Hoechst 33342 staining. Cell viability was assessed using the 3-（4, 5-dimethylthiazol-（2）-yl）-2, 5-diphenyl tetrazolium bromide （MTT） assay. Cell apoptosis and the apoptosis-related activation in the HeLa cell line were evaluated by flow cytometry and Western blotting. Results： Oridonin suppressed the proliferation of the HeLa cell line in a dose- and time-dependent fashion. Oridonin treatment downregulated the activation of protein kinase B （Akt）, the expression of forkhead box class O （FOXO） transcription factor, and glycogen synthase kinase 3 （GSK3）. Oridonin also induced the release of cytochrome c accompanied by the activation of caspase-3 and poly-adenosine diphosphate-ribose polymerase cleavage. In addition, Z-D（OMe）-E（OMe）-V-D（OMe）- FMK （z-DEVD-fmk）, an inhibitor of caspases, prevented caspase-3 activation and abrogated oridonin-induced cell death. Finally, oridonin treatment of the HeLa cell line downregulated the expression of the inhibitor of the apoptosis protein. Conclusion： Our results showed that oridonin-induced apoptosis involved several molecular pathways. Oridonin may suppress constitutively activated targets of phosphatidylinositol 3-kinase （Akt, FOXO, and GSK3） in the HeLa cell line, inhibiting the proliferation and induction of caspase-dependent apoptosis.Aim： To investigate the apoptosis-inducing effect of oridonin, a diterpenoid isolated from Rabdosia rubescens, in the human cervical carcinoma HeLa cell line. Methods： A morphological analysis, nuclear condensation, and fragmentation of chromatin were monitored using Hoechst 33342 staining. Cell viability was assessed using the 3-（4, 5-dimethylthiazol-（2）-yl）-2, 5-diphenyl tetrazolium bromide （MTT） assay. Cell apoptosis and the apoptosis-related activation in the HeLa cell line were evaluated by flow cytometry and Western blotting. Results： Oridonin suppressed the proliferation of the HeLa cell line in a dose- and time-dependent fashion. Oridonin treatment downregulated the activation of protein kinase B （Akt）, the expression of forkhead box class O （FOXO） transcription factor, and glycogen synthase kinase 3 （GSK3）. Oridonin also induced the release of cytochrome c accompanied by the activation of caspase-3 and poly-adenosine diphosphate-ribose polymerase cleavage. In addition, Z-D（OMe）-E（OMe）-V-D（OMe）- FMK （z-DEVD-fmk）, an inhibitor of caspases, prevented caspase-3 activation and abrogated oridonin-induced cell death. Finally, oridonin treatment of the HeLa cell line downregulated the expression of the inhibitor of the apoptosis protein. Conclusion： Our results showed that oridonin-induced apoptosis involved several molecular pathways. Oridonin may suppress constitutively activated targets of phosphatidylinositol 3-kinase （Akt, FOXO, and GSK3） in the HeLa cell line, inhibiting the proliferation and induction of caspase-dependent apoptosis.

关 键 词：cervical carcinoma ORIDONIN APOPTOSIS AKT 

分 类 号：R737.33[医药卫生—肿瘤]