Evodiamine-induced human melanoma A375-S2 cell death was mediated by PI3K/Akt/caspase and Fas-L/NF-kappaB signaling pathways and augmented by ubiquitin-proteasome inhibition.
Evodiamine, a major alkaloidal component of Evodiae fructus exhibits anti-tumor activities. We have previously reported that evodiamine has a marked inhibitory effect on IL-1 sensitive human melanoma A375-S2 cells proliferation, and this action might be through inactivation of PI3K signaling. However, the detailed molecular mechanisms of evodiamine-induced cell death remains poorly understood. In present study, we further confirmed that Akt is the main effector molecule involved in this pathway. Evodiamine also led to IkappaBalpha phosphorylation and degradation that reflect translocation of NF-kappaB. Pretreatment of A375-S2 cells with ubiquitin-proteasome inhibitor MG132 was shown to aggregate the evodiamine caused cell death at 24h. In addition, MG132 reduced ERK phosphorylation, increased caspase-3 activation, Fas-L expression and Bcl-2 cleavage in evodiamine-treated A375-S2 cells. These results suggested the PI3K/Akt/caspase and Fas-L/NF-kappaB signaling pathways might account for the responses of A375-S2 cell death induced by evodiamine, and these signals could be augmented by ubiquitin-proteasome pathway.
Wang
Che
C
Department of Pharmacy, College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, China. wangche126@yahoo.com.cn
Li
Song
S
Wang
Min-wei
MW
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010936:Plant Extracts / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D025801:Ubiquitin / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D004396:Coloring Agents; D053222:Fas Ligand Protein; D016328:NF-kappa B; D010936:Plant Extracts; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D025801:Ubiquitin; C049639:evodiamine; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases; C022616:thiazolyl blue