ß-Elemene inhibits proliferation of human glioblastoma cells and causes cell-cycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6.
ß-elemene, a natural plant drug extracted from Curcuma wenyujin, has shown a strong anti-glioblastoma effect. However, the antitumor mechanism of ß-elemene remains unclear. Mitogen-activated protein kinase kinase-3 (MKK3) and -6 (MKK6) can regulate cellular growth, fission, differentiation and apoptosis. To illustrate the role of MKK3 and MKK6 in the anti-glioblastoma proliferation effect of ß-elemene, U87 cells were treated with ß-elemene at various doses or for different times, and then phosphorylated MKK3 (p-MKK3), phosphorylated MKK6 (p-MKK6), MKK3 and MKK6 were detected by Western blot assay. After transient transfection with dominant-negative mutant plasmids of MKK3 and MKK6, cell viability and cell cycle stage were determined by methyl thiazolyl tetrazolium assay and flow cytometry, respectively. Results showed that ß-elemene inhibited the proliferation of U87 glioblastoma cells and arrested them in G0/G1 phase through up-regulating p-MKK3 and p-MKK6 levels. In contrast, inhibition of MKK3 and MKK6 reversed the antitumor effect of ß-elemene. Furthermore, when either MKK3 or MKK6 was inhibited by a dominant-negative plasmid, the other was compensatorily activated in the presence of ß-elemene. Taken together, our findings indicate that mutually compensatory activation of MKK3 and MKK6 mediates the anti-glioblastoma effect of ß-elemene. MKK3 and MKK6 might be two putative targets for molecular therapy against glioblastoma.
Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, No 222 Zhong Shan Road, Dalian 116011, PR China.
Tingzhun
T
Zhu
Yongshun
Y
Zhao
Jianing
J
Zhang
Longjie
L
Li
Lijuan
L
Zou
Yiqun
Y
Yao
Yinghui
Y
Xu
D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D012717:Sesquiterpenes; C445979:beta-elemene; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human