Calcium-stimulated mitogen-activated protein kinase activation elicits Bcl-xL downregulation and Bak upregulation in notexin-treated human neuroblastoma SK-N-SH cells.
Notechis scutatus scutatus notexin induced apoptotic death of SK-N-SH cells accompanied with downregulation of Bcl-xL, upregulation of Bak, mitochondrial depolarization, and ROS generation. Upon exposure to notexin, Ca(2+)-mediated JNK and p38 MAPK activation were observed in SK-N-SH cells. Production of ROS was a downstream event followed by Ca(2+)-mediated mitochondrial alteration. Notexin-induced cell death, mitochondrial depolarization, and ROS generation were suppressed by SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor). Moreover, phospho-p38 MAPK and phospho-JNK were proved to be involved in Bcl-xL degradation, and overexpression of Bcl-xL attenuated the cytotoxic effect of notexin. Bak upregulation was elicited by p38 MAPK-mediated ATF-2 activation and JNK-mediated c-Jun activation. Suppression of Bak upregulation by ATF-2 siRNA or c-Jun siRNA attenuated notexin-evoked mitochondrial depolarization and rescued viability of notexin-treated cells. Taken together, our data indicate that notexin-induced apoptotic death of SK-N-SH cells is mediated through mitochondrial alteration triggering by Ca(2+)-evoked p38 MAPK/ATF-2 and JNK/c-Jun signaling pathways.
Institute of Biomedical Sciences, National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Ku-Chung
KC
Chen
Wen-Hsin
WH
Liu
Pei-Hsiu
PH
Kao
Long-Sen
LS
Chang
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology*; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004546:Elapid Venoms / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051698:Activating Transcription Factor 2; D000873:Anthracenes; D004546:Elapid Venoms; D007093:Imidazoles; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C432165:pyrazolanthrone; C005082:notexin; D004533:Egtazic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053453:Caspase 9; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D002118:Calcium