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丙戊酸对神经母细胞瘤和胶质母细胞瘤细胞系中内在、外在及JAK/STAT信号通路的影响。

The effect of valproic acid on intrinsic, extrinsic, and JAK/STAT pathways in neuroblastoma and glioblastoma cell lines.

作者信息

Sanaei Masumeh, Kavoosi Fraidoon

机构信息

Non-Communicable Diseases Research Center, Jahrom University of Medical Sciences, Jahrom, I.R. Iran.

出版信息

Res Pharm Sci. 2022 Jul 14;17(4):392-409. doi: 10.4103/1735-5362.350240. eCollection 2022 Aug.

DOI:10.4103/1735-5362.350240
PMID:36034083
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9400463/
Abstract

BACKGROUND AND PURPOSE

Epigenetics has been defined as the study of mitotically heritable alterations in gene expression that are not caused by changes in DNA sequence. Epigenetic-mediated silencing of a gene includes genomic imprinting, histone deacetylation, DNA methylation, and RNA-associated silencing. Cell growth and cell proliferation are inhibited by some histone deacetylase and histone inhibitors. This study was designed to investigate the effect of valproic acid (VPA) on extrinsic, intrinsic, and the Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathways in neuroblastoma and glioblastoma cell lines.

EXPERIMENTAL APPROACH

The neuroblastoma and glioblastoma cells were cultured and treated with VPA. MTT assay was done to determine cell viability. Besides, a flow cytometry assay was performed to determine apoptotic cells and finally, the relative gene expression level was evaluated by qRT-PCR.

FINDINGS / RESULTS: VPA changed the expression level of the genes of the extrinsic, intrinsic, and JAK/STAT pathways which induced cell apoptosis and inhibited cell growth in the neuroblastoma and glioblastoma cells. In the neuroblastoma cell lines, VPA upregulated the expression level of FAS, FAS-L, DR4, DR5, and TRAIL genes significantly. Additionally, it significantly up-regulated the expression level of Bak, Bax, and Bim genes and down-regulated the expression level of Bcl-xL, Bcl-2, and Mcl-1 genes in both neuroblastoma and glioblastoma cell lines.

CONCLUSION AND IMPLICATIONS

VPA induced cell apoptosis through extrinsic, intrinsic, and JAK/STAT pathways.

摘要

背景与目的

表观遗传学被定义为对基因表达中可通过有丝分裂遗传的改变的研究，这些改变并非由DNA序列变化引起。基因的表观遗传介导沉默包括基因组印记、组蛋白去乙酰化、DNA甲基化和RNA相关沉默。一些组蛋白去乙酰化酶和组蛋白抑制剂可抑制细胞生长和细胞增殖。本研究旨在探讨丙戊酸（VPA）对神经母细胞瘤和胶质母细胞瘤细胞系中外源、内源以及Janus激酶（JAK）-信号转导子和转录激活子（STAT）通路的影响。

实验方法

培养神经母细胞瘤和胶质母细胞瘤细胞并用VPA处理。采用MTT法测定细胞活力。此外，进行流式细胞术检测以确定凋亡细胞，最后通过qRT-PCR评估相对基因表达水平。

研究结果

VPA改变了外源、内源和JAK/STAT通路相关基因的表达水平，诱导神经母细胞瘤和胶质母细胞瘤细胞凋亡并抑制细胞生长。在神经母细胞瘤细胞系中，VPA显著上调FAS、FAS-L、DR4、DR5和TRAIL基因的表达水平。此外，在神经母细胞瘤和胶质母细胞瘤细胞系中，它均显著上调Bak、Bax和Bim基因的表达水平，下调Bcl-xL、Bcl-2和Mcl-1基因的表达水平。

结论与意义

VPA通过外源、内源和JAK/STAT通路诱导细胞凋亡。

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