Ginkgolide B induces apoptosis via activation of JNK and p21-activated protein kinase 2 in mouse embryonic stem cells.
Ginkgolide B (GKB), the major active component of Ginkgo biloba extracts, can both stimulate and inhibit apoptotic signaling. We previously showed that ginkgolide treatment of mouse blastocysts induces apoptosis, decreases cell numbers, retards the proliferation and development of mouse embryonic stem cells and blastocysts in vitro, and causes developmental injury in vivo. However, the precise molecular mechanisms underlying its actions are currently unknown. Here, our study further revealed that GKB induced apoptotic biochemical changes, including activation of JNK, caspase-3, and p21-activated protein kinase 2 (PAK2), in ESC-B5 mouse embryonic stem cells. Treatment of ESC-B5 cells with a JNK-specific inhibitor (SP600125) reduced GKB-induced activation of both JNK and caspase-3, indicating that JNK activity is required for GKB-induced caspase activation. Experiments using caspase-3 inhibitors and antisense oligonucleotides against PAK2 showed that caspase-3 activation is required for PAK2 activation and both of these activations are required for GKB-induced apoptosis in ESC-B5 cells.
Hsuuw
Yan-Der
YD
Department of Life Science, National Pingtung University of Science and Technology, Pingtung, Taiwan.
Kuo
Tzong-Fu
TF
Lee
Kun-Hsiung
KH
Liu
Yen-Chih
YC
Huang
Yu-Ting
YT
Lai
Ching-Yu
CY
Chan
Wen-Hsiung
WH
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D046934:Ginkgolides / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D014162:Transfection; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D000873:Anthracenes; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D046934:Ginkgolides; D007783:Lactones; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C432165:pyrazolanthrone; C045856:ginkgolide B; C515909:Pak2 protein, mouse; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3