title: 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.
authors.affiliation: Department of Neurosurgery, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110840, P.R. China.
authors.forename: Ting-Zhun
authors.initials: TZ
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110840, P.R. China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Li
authors.affiliation: Health Care Centre, Shenyang Entry-Exit Inspection and Quarantine Bureau, Shenyang, Liaoning 110016, P.R. China.
authors.forename: Li-Han
authors.initials: LH
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110840, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
authors.affiliation: Department of Neurosurgery, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110840, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110840, P.R. China.
authors.forename: Guo-Biao
authors.initials: GB
authors.lastname: Liang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D030024:Curcuma / Q000737:chemistry / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D020904:Glia Maturation Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012717:Sesquiterpenes / Q000633:toxicity*; D000077022:Survivin; D000077204:Temozolomide
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D005419:Flavonoids; D020904:Glia Maturation Factor; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D000077022:Survivin; C445979:beta-elemene; D003606:Dacarbazine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077204:Temozolomide