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

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.