Oridonin Induces Human Malignant Melanoma A375-S2 Cell Death Through Inhibiting IGF-1 Receptor Signaling

Our previous studies indicated that Oridonin, a diterpenoid isolated from Rabdosia rubescens, induced human malignant melanoma A375-S2 cell apoptosis.In this study we investigated whether the proapoptotic effect of Oridonin on A375-S2 cells would depend on interference with function of the insulin-like growth factor 1 (IGF-1) receptor, a plasma membrane receptor critical for survival or antiapoptotic ability in melanoma cells. We found that IGF-1 receptor (IGF-IR) signaling was a potential survival pathway against a low concentration of 20μM oridonin-induced apoptosis in A375-S2 cells. 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 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 40μM (IC50 at 24 h) Oridonin, A375-S2 cells could not be protected by IGF-1 from apoptosis, accompanied by severe impairment of IGF-IR expression. Therefore, we concluded that the proapoptotic activity of Oridonin was partially attributed to its repression of IGF-IR signaling. In addition, p53 was supposed to be a pivotal transducer of proapoptotic and survival signaling pathway in this system.