Modes of activation of mitogen-activated protein kinases and their roles in cepharanthine-induced apoptosis in human leukemia cells

• Published in: Cellular signalling 2002-06, Vol.14 (6), p.509-515
• Main Authors: Wu, Jianghong, Suzuki, Haruhiko, Akhand, Anwarul A., Zhou, Yan-Wen, Hossain, Khaled, Nakashima, Izumi
• Format: Article
• Language: English
• Subjects: Alkaloids - antagonists & inhibitors; Alkaloids - pharmacology; Amino Acid Chloromethyl Ketones - pharmacology; Antineoplastic Agents, Phytogenic - antagonists & inhibitors; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Benzylisoquinolines; Caspase Inhibitors; Cepharanthine; Cysteine Proteinase Inhibitors - pharmacology; Enzyme Activation; Enzyme Inhibitors - pharmacology; ERK; Human leukemia cell; Humans; JNK; Jurkat Cells; K562 Cells; Kinetics; Leukemia - enzymology; Leukemia - pathology; MAP kinase; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - physiology; p38; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein-Tyrosine Kinases - antagonists & inhibitors; Transcription Factors - metabolism
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/S0898-6568(01)00278-9

We previously showed that cepharanthine (CEP), a biscoclaurine alkaloid, induces caspase-dependent and Fas-independent apoptosis in Jurkat and K562 human leukemia cells. In the present study, we investigated the effect of CEP on three groups of human mitogen-activated protein kinases (MAPKs) in relation to CEP-induced apoptosis. CEP, at the concentration required for and at the time of induction of apoptosis, activated MAPKs p38 in both Jurkat and K562 cells and activated extracellular signal-regulated kinases (ERKs) only in K562 cells. However, CEP treatment did not trigger c-Jun NH 2-terminal kinases (JNKs) activation. CEP increased the expression and phosphorylation levels of c-Jun and ATF-2 transcription factors. zVAD-fmk, a general caspase inhibitor, did not inhibit CEP-triggered p38 activation in Jurkat and K562 cells or ERK activation in K562 cells. Unexpectedly, pretreatment with a specific p38 inhibitor, SB203580, promoted CEP-induced apoptosis and caspase activation in Jurkat and K562 cells, whereas pretreatment with an MEK-1 inhibitor PD98059 inhibited CEP-induced apoptosis and caspase activation in K562 cells. A selective tyrosine kinase inhibitor, herbimycin A, which completely inhibited CEP-triggered ERKs activation, clearly promoted CEP-induced c-Jun expression and phosphorylation. Our results suggest that each of the three groups of MAP family members is uniquely involved in the CEP-mediated signal cascades in two different leukemia cell lines for inducing/regulating caspase activation and DNA fragmentation.