Gamma-tocotrienol (GTT) and hydroxychavicol (HC) exhibit anticancer activity in glioma cancer cells, where the combination of GTT + HC was shown to be more effective than single agent. The aim of this study was to determine the effect of GTT + HC by measuring the cell cycle progression, migration, invasion, and colony formation of glioma cancer cells and elucidating the changes in gene expression mitigated by GTT + HC that are critical to the chemoprevention of glioma cell lines 1321N1 (grade II), SW1783 (grade III), and LN18 (grade IV) using high-throughput RNA sequencing (RNA-seq). Results of gene expression levels and alternative splicing transcripts were validated by qPCR. Exposure of glioma cancer cells to GTT + HC for 24 h promotes cell cycle arrest at G2M and S phases and inhibits cell migration, invasion, and colony formation of glioma cancer cells. The differential gene expression induced by GTT + HC clustered into response to endoplasmic reticulum (ER) stress, cell cycle regulations, apoptosis, cell migration/invasion, cell growth, and DNA repair. Subnetwork analysis of genes altered by GTT + HC revealed central genes, ATF4 and XBP1. The modulation of EIF2AK3, EDN1, and FOXM1 were unique to 1321N1, while CSF1, KLF4, and FGF2 were unique to SW1783. PLK2 and EIF3A gene expressions were only altered in LN18. Moreover, GTT + HC treatment dynamically altered transcripts and alternative splicing expression. GTT + HC showed therapeutic potential against glioma cancer as evident by the inhibition of cell cycle progression, migration, invasion, and colony formation of glioma cancer cells, as well as the changes in gene expression profiles with key targets in ER unfolded protein response pathway, apoptosis, cell cycle, and migration/invasion.

中文翻译：

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转录组分析揭示了γ-生育三烯酚和羟基查韦尔的组合在预防1321N1，SW1783和LN18胶质瘤癌细胞增殖中的分子机制。

γ-生育三烯酚（GTT）和羟基查韦科尔（HC）在神经胶质瘤癌细胞中表现出抗癌活性，其中GTT + HC的组合被证明比单一药物更有效。这项研究的目的是通过测量神经胶质瘤癌细胞的细胞周期进程，迁移，侵袭和集落形成，并阐明由GTT + HC缓解的基因表达变化对化学预防至关重要，从而确定GTT + HC的作用使用高通量RNA测序（RNA-seq）对神经胶质瘤细胞株1321N1（II级），SW1783（III级）和LN18（IV级）进行检测。通过qPCR验证基因表达水平和选择性剪接转录本的结果。胶质瘤癌细胞暴露于GTT + HC 24小时可促进细胞周期停滞在G2M和S期，并抑制细胞迁移，侵袭，和胶质瘤癌细胞的集落形成。GTT + HC诱导的差异基因表达集中于对内质网（ER）压力，细胞周期调控，凋亡，细胞迁移/侵袭，细胞生长和DNA修复的反应。对GTT + HC改变的基因进行子网分析，发现了中心基因，ATF4和XBP1。的调制EIF2AK3，EDN1和FOXM1所特有的1321N1，而CSF1，KLF4和FGF2所特有的SW1783。PLK2和EIF3A基因表达仅在LN18中改变。此外，GTT + HC处理可动态改变转录本和选择性剪接表达。GTT + HC显示出对神经胶质瘤癌症的治疗潜力，这通过抑制神经胶质瘤癌细胞的细胞周期进程，迁移，侵袭和集落形成以及ER表达中关键靶点的基因表达谱的改变而得以证明，细胞凋亡，细胞周期和迁移/侵袭。