Roles of p38 and JNK mitogen-activated protein kinase pathways during cantharidin-induced apoptosis in U937 cells.
Cantharidin is an active compound from blister beetles traditionally used for the treatment of cancer. It is known to exert its antitumor activity by inducing apoptosis in cancer cells. However, its signaling pathway still remains unclear. Therefore, we investigated the roles of the mitogen-activated protein kinases (MAPKs) and the tumor suppressor gene, p53, during cantharidin-induced apoptosis in U937 human leukemic cells. Cantharidin effectively activated ERK-1/2, p38 and JNK in U937 cells in a time- and dose-dependent manner. Cantharidin also exhibited a strong cytotoxicity and induced apoptosis in U937 cells. For the evaluation of the role of MAPKs, PD98059, SB202190 and SP600125 were used as MAPK inhibitors for ERK-1/2, p38 and JNK. PD98059 did not affect cantharidin-induced cytotoxicity and apoptosis, whereas SB202190 and SP600125 significantly interfered with cytotoxic and apoptotic activities induced by cantharidin. Cantharidin alone induced the apoptosis by phosphorylation of p53, up-regulation of downstream target genes, MDM2 and p21 and also cleaved caspase-3, whereas SB202190 and SP600125 caused the down-regulation of p53, MDM-2, p21 and cleaved caspase-3 after a co-treatment with cantharidin. Similarly, SB202190 and SP600125 significantly disturbed the caspase-3 activity after a co-treatment with cantharidin by colorimetric assay. Taken together, these results suggest that cantharidin can induce apoptosis by activation of p38 and JNK MAP kinase pathways associated with p53 and caspase-3.
Huh
Jeong-Eun
JE
Department of Oncology, Graduate School of East-West Medical Science, Kyunghee University, Yongin 449-701, South Korea.
Kang
Kyung-Sun
KS
Chae
Chanhee
C
Kim
Hyung-Min
HM
Ahn
Kyoo-Seok
KS
Kim
Sung-Hoon
SH
D017209:Apoptosis / Q000502:physiology*; D002193:Cantharidin / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002193:Cantharidin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one