Oridonin induces G2/M arrest and apoptosis via activating ERK-p53 apoptotic pathway and inhibiting PTK-Ras-Raf-JNK survival pathway in murine fibrosarcoma L929 cells.
Oridonin was reported to induce L929 cell apoptosis via ROS-mediated mitochondrial and ERK pathways; however, the precise mechanisms by which oridonin induces cell death remain unclear. Herein, we found that oridonin treatment induced an increase in G(2)/M phase cell percentage. And, G(2)/M phase arrest was associated with down-regulation of cell cycle related cdc2, cdc25c and cyclinB levels, as well as up-regulation of p21 and p-cdc2 levels. In addition, we discovered that interruption of p53 activation decreased oridonin-induced apoptosis, and blocking ERK by specific inhibitors or siRNA suppressed oridonin-induced p53 activation. Moreover, inhibition of PTK, protein kinase C, Ras, Raf or JNK activation increased oridonin-induced apoptosis. Also, the level of Ras, Raf or JNK was down-regulated by oridonin, and the inhibition of PTK, Ras, Raf activation decreased p-JNK level. In conclusion, oridonin induces L929 cell G(2)/M arrest and apoptosis, which is regulated by promoting ERK-p53 apoptotic pathway and suppressing PTK-mediated survival pathway.
Cheng
Yan
Y
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China. chengyan0677@163.com
Qiu
Feng
F
Ye
Yuan-chao
YC
Tashiro
Shin-ichi
S
Onodera
Satoshi
S
Ikejima
Takashi
T
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000502:physiology; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors
D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C011959:oridonin; D011505:Protein-Tyrosine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D018631:ras Proteins