title: Taiwan cobra phospholipase A2-elicited JNK activation is responsible for autocrine fas-mediated cell death and modulating Bcl-2 and Bax protein expression in human leukemia K562 cells.
abstract: Phospholipase A(2) (PLA(2)) from Naja naja atra venom induced apoptotic death of human leukemia K562 cells. Degradation of procaspases, production of tBid, loss of mitochondrial membrane potential, Bcl-2 degradation, mitochondrial translocation of Bax, and cytochrome c release were observed in PLA(2)-treated cells. Moreover, PLA(2) treatment increased Fas and FasL protein expression. Upon exposure to PLA(2), activation of p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun NH(2)-terminal kinase) was found in K562 cells. SB202190 (p38 MAPK inhibitor) pretreatment enhanced cytotoxic effect of PLA(2) and led to prolonged JNK activation, but failed to affect PLA(2)-induced upregulation of Fas and FasL protein expression. Sustained JNK activation aggravated caspase8/mitochondria-dependent death pathway, downregulated Bcl-2 expression and increased mitochondrial translocation of Bax. SP600125 (JNK inhibitor) abolished the cytotoxic effect of PLA(2) and PLA(2)-induced autocrine Fas death pathway. Transfection ASK1 siRNA and overexpression of dominant negative p38alpha MAPK proved that ASK1 pathway was responsible for PLA(2)-induced p38 MAPK and JNK activation and p38alpha MAPK activation suppressed dynamically persistent JNK activation. Downregulation of FADD abolished PLA(2)-induced procaspase-8 degradation and rescued viability of PLA(2)-treated cells. Taken together, our results indicate that JNK-mediated autocrine Fas/FasL apoptotic mechanism and modulation of Bcl-2 family proteins are involved in PLA(2)-induced death of K562 cells.
authors: Institute of Biomedical Sciences, National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors: Ku-Chung
authors: KC
authors: Chen
authors: Wen-Hsin
authors: WH
authors: Liu
authors: Long-Sen
authors: LS
authors: Chang
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D004546:Elapid Venoms / Q000201:enzymology / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D054467:Phospholipases A2 / Q000378:metabolism* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D004546:Elapid Venoms; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D048670:MAP Kinase Kinase 4; D054467:Phospholipases A2