Objective:A high-fat,low-carbohydrate ketogenic diet has been used to treat malignant glioma,in which the Raf/MEK/ERK signaling pathway is overactivated.However,whether the Raf/MEK/ERK signaling pathway is involved in...Objective:A high-fat,low-carbohydrate ketogenic diet has been used to treat malignant glioma,in which the Raf/MEK/ERK signaling pathway is overactivated.However,whether the Raf/MEK/ERK signaling pathway is involved in the therapeutic effect of ketone bodies remains unknown.In this study,we investigated the effects of a major ketone body,3-hydroxybutyric acid(3-HBA),on the proliferation and metastasis of malignant glioblastoma cells and the underlying mechanism.Methods:Two human malignant glioblastoma cell lines(U87 and U251)were treated with different concentrations of 3-HBA with or without the Raf inhibitor PAF C-16 for 24 h.Cell proliferation,cell cycle,cell invasion,and phospholipase D1(PLD1)activity were determined.Protein and gene expression levels of Raf/MEK/ERK signaling pathway members were examined.Results:3-HBA significantly decreased cell proliferation,invasion,and intracellular PLD1 activity in both U87 and U251 glioblastoma cell lines.3-HBA treatment significantly increased the proportion of cells in the G1 phase and decreased the proportion of cells in S phase in U87 cells.In the U251 line,the proportion of treated cells in S phase was increased and proportion of cells in G2 was decreased.3-HBA treatment also significantly decreased the protein expression levels of Raf,MEK,p-MEK,ERK,p-ERK,and PLD1 while increasing p53 expression;an effect that was similar to treatment with the Raf inhibitor.Co-treatment of 3-HBA with the Raf inhibitor further enhanced the effects of the 3-HBA in both cell lines.Conclusion:We confirmed that a ketogenic microenvironment can inhibit glioma cell proliferation and invasion by downregulating the expression of PLD1 through the Raf/MEK/ERK signaling pathway.展开更多
Ras/Raf/MEK/细胞外信号调节蛋白激酶（extracellular signal-regulated protein kinase,ERK）信号通路又称ERK通路,该通路主要由一个三级酶联功能单位构成,其通过＂瀑布式＂的级联反应,将细胞外刺激信号传至细胞内,引起一系列细胞反应...Ras/Raf/MEK/细胞外信号调节蛋白激酶（extracellular signal-regulated protein kinase,ERK）信号通路又称ERK通路,该通路主要由一个三级酶联功能单位构成,其通过＂瀑布式＂的级联反应,将细胞外刺激信号传至细胞内,引起一系列细胞反应,从而调控细胞增殖、分化、凋亡、转移等功能。展开更多
细胞在接受特定的细胞外信号刺激后会产生相应的特异性生理应答。Ras／Raf／MEK／ERK信号级联通路是一条可被广泛激活的有丝分裂原活化蛋白激酶（mitogen—activated protein kinase，MAPK）通路，它能将细胞外信号传递入细胞核内，引...细胞在接受特定的细胞外信号刺激后会产生相应的特异性生理应答。Ras／Raf／MEK／ERK信号级联通路是一条可被广泛激活的有丝分裂原活化蛋白激酶（mitogen—activated protein kinase，MAPK）通路，它能将细胞外信号传递入细胞核内，引起细胞内特异蛋白的表达谱变化，从而影响细胞命运。展开更多
基金supported by the Clinical Innovation Guidance Plan of the Department of Science and Technology of Hunan Province(No.2018SK51502)a Postgraduate Scientific Research Innovation Project of Hunan Province(No.CX20210977)+1 种基金Key Guiding Subjects of the Hunan Provincial Health Commission(No.20201912)the Natural Science Foundation of Hunan Province(Nos.2020JJ8029,2018JJ3461).
文摘Objective:A high-fat,low-carbohydrate ketogenic diet has been used to treat malignant glioma,in which the Raf/MEK/ERK signaling pathway is overactivated.However,whether the Raf/MEK/ERK signaling pathway is involved in the therapeutic effect of ketone bodies remains unknown.In this study,we investigated the effects of a major ketone body,3-hydroxybutyric acid(3-HBA),on the proliferation and metastasis of malignant glioblastoma cells and the underlying mechanism.Methods:Two human malignant glioblastoma cell lines(U87 and U251)were treated with different concentrations of 3-HBA with or without the Raf inhibitor PAF C-16 for 24 h.Cell proliferation,cell cycle,cell invasion,and phospholipase D1(PLD1)activity were determined.Protein and gene expression levels of Raf/MEK/ERK signaling pathway members were examined.Results:3-HBA significantly decreased cell proliferation,invasion,and intracellular PLD1 activity in both U87 and U251 glioblastoma cell lines.3-HBA treatment significantly increased the proportion of cells in the G1 phase and decreased the proportion of cells in S phase in U87 cells.In the U251 line,the proportion of treated cells in S phase was increased and proportion of cells in G2 was decreased.3-HBA treatment also significantly decreased the protein expression levels of Raf,MEK,p-MEK,ERK,p-ERK,and PLD1 while increasing p53 expression;an effect that was similar to treatment with the Raf inhibitor.Co-treatment of 3-HBA with the Raf inhibitor further enhanced the effects of the 3-HBA in both cell lines.Conclusion:We confirmed that a ketogenic microenvironment can inhibit glioma cell proliferation and invasion by downregulating the expression of PLD1 through the Raf/MEK/ERK signaling pathway.
文摘Ras/Raf/MEK/细胞外信号调节蛋白激酶（extracellular signal-regulated protein kinase,ERK）信号通路又称ERK通路,该通路主要由一个三级酶联功能单位构成,其通过＂瀑布式＂的级联反应,将细胞外刺激信号传至细胞内,引起一系列细胞反应,从而调控细胞增殖、分化、凋亡、转移等功能。
文摘细胞在接受特定的细胞外信号刺激后会产生相应的特异性生理应答。Ras／Raf／MEK／ERK信号级联通路是一条可被广泛激活的有丝分裂原活化蛋白激酶（mitogen—activated protein kinase，MAPK）通路，它能将细胞外信号传递入细胞核内，引起细胞内特异蛋白的表达谱变化，从而影响细胞命运。
