Oridonin induces human melanoma A375-S2 cell death partially through inhibiting insulin-like growth factor 1 receptor signaling.
Our previous studies indicated that oridonin, a diterpenoid isolated from Rabdosia rubescens, induced human melanoma A375-S2 cell apoptosis. In this study, we investigated whether the proapoptotic effect of oridonin on A375-S2 cells would depend on an interference with function of the insulin-like growth factor 1 (IGF-1) receptor, a plasma membrane receptor critical for the survival or antiapoptotic ability in melanoma cells. We found that IGF-1 receptor (IGF-1R) signaling was a potential survival pathway against a low concentration of 20 micromol/L oridonin-induced apoptosis in A375-S2 cells. The activation of Ras or its downstream effector p38 mitogen-activated protein kinase (p38 MAPK) was shown to be necessary for IGF-1-mediated protection, but the activation of phosphatidylinositol-3-OH kinase (PI3 kinase) or extracellular signal-regulated kinase (ERK) did not correlate with the regulation of survival. However, in the presence of 40 micromol/L (IC50 at 24 h) oridonin, A375-S2 cells could not be protected by IGF-1 from apoptosis, accompanied by a severe impairment of IGF-1R expression. Therefore, we concluded that the proapoptotic activity of oridonin was partially attributed to its repression of IGF-1R signaling. In addition, p53 was supposed to be a pivotal transducer of proapoptotic and survival signaling pathway in this system.
Wang
Hong-Jun
HJ
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, China.
Li
Dan
D
Yang
Fan-Yi
FY
Tashiro
Shin-Ichi
S
Onodera
Satoshi
S
Ikejima
Takashi
T
D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D045786:Diterpenes, Kaurane / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015394:Molecular Structure; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D045786:Diterpenes, Kaurane; C011959:oridonin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D048051:p38 Mitogen-Activated Protein Kinases