β-Elemene inhibits proliferation through crosstalk between glia maturation factor β and extracellular signal‑regulated kinase 1/2 and impairs drug resistance to temozolomide in glioblastoma cells

Zhu,Ting-Zhun; Li,Xiao-Ming; Luo,Li-Han; Xu,Ying-Hui; Cao,Peng; Liu,Yang; Liang,Guo-Biao

doi:10.3892/mmr.2014.2273

β-Elemene inhibits proliferation through crosstalk between glia maturation factor β and extracellular signal‑regulated kinase 1/2 and impairs drug resistance to temozolomide in glioblastoma cells

Authors:
- Ting-Zhun Zhu
- Xiao-Ming Li
- Li-Han Luo
- Ying-Hui Xu
- Peng Cao
- Yang Liu
- Guo-Biao Liang
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Affiliations: Department of Neurosurgery, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110840, P.R. China, Health Care Centre, Shenyang Entry-Exit Inspection and Quarantine Bureau, Shenyang, Liaoning 110016, P.R. China, Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Published online on: May 27, 2014 https://doi.org/10.3892/mmr.2014.2273
Pages: 1122-1128

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Abstract

β-elemene, a plant-derived drug extracted from Curcuma wenyujin, has demonstrated marked antiproliferative effects on glioblastoma, while toxicity remains low. However, the underlying molecular mechanisms of the antitumor activity of β-elemene remain to be elucidated. Previously, it was identified that the glia maturation factor β (GMFβ)/mitogen-activated protein kinase kinase (MAPK) 3/6/p38 pathway participates in the antiproliferative activity of β-elemene on glioblastoma. In the present study, in order to illustrate the association of GMFβ and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, U87 and U251 cells were treated with β-elemene at various doses and for different durations, and the expression of phosphorylated ERK1/2 (p-ERK1/2), ERK1/2, B-cell lymphoma 2 (Bcl-2), Bcl2-associated X and survivin was examined by western blot analysis. Following treatment with β-elemene and the ERK1/2 inhibitor PD98059, U87 cell viability was evaluated using a Cell Counting Kit-8 (CCK-8) assay, and the expression levels of Bcl-2 and survivin were examined by western blot analysis. GMFβ was then downregulated by RNA interference in β-elemene-treated U87 cells, and the effect of this on the expression of ERK1/2 and p-ERK1/2 was determined by western blot analysis. Finally, the chemosensitisation of U87 cells to temozolomide (TMZ) through β-elemene was examined using the CCK-8 assay. The results demonstrated that β-elemene inhibited the proliferation of U87 glioblastoma cells through the GMFβ‑dependent inactivation of the ERK1/2-Bcl-2/survivin pathway. Furthermore, inhibition of ERK1/2 by PD98059 enhanced the antitumor effect of β-elemene and impaired the expression levels of Bcl-2 and survivin. β-elemene also increased the sensitivity of U87 glioblastoma cells to the chemotherapeutic TMZ, which was synergistically enhanced by PD98059. In conclusion, these results suggested that GMFβ-dependent inactivation of the ERK1/2-Bcl-2/survivin pathway mediated the antiproliferative effect of β-elemene on glioblastoma. Therefore, β-elemene is a promising chemosensitizer or adjuvant therapeutic for TMZ against glioblastoma brain tumors.

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