Fibroblast growth factor-2 suppresses oridonin-induced L929 apoptosis through extracellular signal-regulated kinase-dependent and phosphatidylinositol 3-kinase-independent pathway.
Oridonin, isolated from Rabdosia rubescences, has been reported to exert cytotoxic effects on L929 cells. In this study, we investigated the mechanisms of FGF-2 protection of L929 cells from oridonin-induced apoptosis. Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signal did not mediate this effect because the PI3K inhibitor wortmannin failed to reverse this protection and PKB activation was not observed in this process. In contrast, the extracellular signal-regulated kinase (ERK) was responsible for this rescue because its inhibition abolished the protective effect of fibroblast growth factor (FGF)-2. ERK had dual regulatory functions: mediating cell apoptosis or preventing cells from initiating the apoptotic response by phosphorylation or promoting expression of Bcl-2 in dependence of different stimuli. In L929 cells treated with oridonin alone, the activated ERK decreased the ratio of Bcl-2/Bax by mediating the phosphorylation of Bcl-2, resulting in apoptosis; the Ras inhibitor manumycin A and Raf inhibitor GW5074 failed to inhibit this apoptosis, indicating that there is a signal other than Ras/Raf pathway activated ERK. However, in the presence of FGF-2, Bcl-2 phosphorylation was blocked, and the Ras/Raf/ERK signal pathway was activated and protected against the oridonin-induced apoptosis by the alternative function of promoting of Bcl-2 expression.
Huang
Jian
J
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, China.
Wu
Lijun
L
Tashiro
Shin-ichi
S
Onodera
Satoshi
S
Ikejima
Takashi
T
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004224:Diterpenes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D045786:Diterpenes, Kaurane / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D019254:Genes, bcl-2 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D010636:Phenols / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D048490:raf Kinases / Q000037:antagonists & inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D045786:Diterpenes, Kaurane; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D007211:Indoles; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D048490:raf Kinases; C011959:oridonin; C054474:manumycin; C489251:5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone