JNK and ERK mitogen-activated protein kinases mediate THDA-induced apoptosis in K562 cells.
2-(6-(2-thieanisyl)-3(Z)-hexen-1, 5-diynyl) aniline (THDA), an enediyne compound, was identified in our laboratory as a novel antineoplastic agent against human leukemia K562 cells. THDA-induced apoptosis was associated with the upregulation of Bax, downregulation of X-linked inhibitor of apoptosis (XIAP), as well as the activation of caspase-3 and caspase-9. In addition, the mitogen-activated protein family kinases, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) kinases, and the transcription factor c-Jun were all activated by phosphorylation after 6 h exposure to THDA. Phosphorylation (activation) of JNK and ERK kinases by THDA was blocked by an ERK inhibitor, PD98059, or a JNK inhibitor, JNK-1, respectively, suggesting that THDA-induced apoptosis in K562 cells is ERK and JNK dependent. Moreover, the blockade of ERK and JNK also attenuated the modulation of Bax and XIAP, as well as the activation of caspase-3 and caspase-9 induced by THDA. These findings suggest that the activation of JNK and ERK is involved in the THDA-induced apoptosis of K562 cells. Therefore, this investigation, for the first time, uncovered the biological properties of this novel antitumor enediyne.
Yang
Sheng-Huei
SH
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Wu
Zchong-Zcho
ZZ
Chien
Ching-Ming
CM
Lo
Yu-Hsiang
YH
Wu
Ming-Jung
MJ
Chang
Long-Sen
LS
Lin
Shinne-Ren
SR
D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D053281:Enediynes / Q000494:pharmacology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C516307:2-(6-(2-thieanisyl)-3-hexen-1,5-diynyl)aniline; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C494826:BAX protein, human; D053281:Enediynes; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D053453:Caspase 9