Transcriptome analysis reveals the molecular mechanisms of combined gamma-tocotrienol and hydroxychavicol in preventing
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ORIGINAL ARTICLE
Transcriptome analysis reveals the molecular mechanisms of combined gamma-tocotrienol and hydroxychavicol in preventing the proliferation of 1321N1, SW1783, and LN18 glioma cancer cells Amirah Abdul Rahman 1,2
&
Norfilza Mohd Mokhtar 3 & Roslan Harun 4 & Rahman Jamal 2 & Wan Zurinah Wan Ngah 5
Received: 26 September 2018 / Accepted: 31 July 2019 # University of Navarra 2019
Abstract 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. Keywords Gamma-tocotrienol . Hydroxychavicol . RNA sequencing . Gene expression . Synergistic effects . Chemoprevention
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13105-019-00699-z) contains supplementary material, which is available to authorized users. * Norfilza Mohd Mokhtar [email protected] Amirah Abdul Rahman [email protected] Roslan Harun [email protected] Rahman Jamal [email protected] Wan Zurinah Wan Ngah [email protected]
1
Department Biochemistry & Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Cawangan Selangor, Kampus Sungai Buloh, Jalan Hospital, 47000 Sungai Buloh, Selangor, Malaysia
2
UKM Medical Molecular Biology Institute (UMBI), UKM Medical Center, Jalan Ya’acob, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Malaysia
3
Department of Physiology, Fa
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