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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
  • Norfilza Mohd MokhtarEmail author
  • Roslan Harun
  • Rahman Jamal
  • Wan Zurinah Wan Ngah
Original Article

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 

Abbreviations

GTT

Gamma-tocotrienol

HC

Hydroxychavicol

ER

Endoplasmic reticulum

MTC

Multiple testing correction

FDR

Benjamini–Hochberg false discovery rate

GSEA

Gene significant enrichment analysis

FET

Fisher exact test

UPR

Unfolded protein response

Notes

Acknowledgments

The authors would like to thank Mohd Faizal Abu Bakar from Malaysian Genome Institute (MGI), Kajang, Malaysia, for his technical assistance with mRNA-Seq analysis and Irni Sahayu Sapian from MGI, Malaysia, for her technical assistance with handling the RNA-Seq equipment.

Authors’ contributions

AAR performed experiments, analysis, and interpretation of data and wrote the manuscript. RJ, RH, and NMM were involved in the general supervision. WZWN designed the study, revised the manuscript, and supervised the study. All authors have read and approved the manuscript.

Funding

This study was supported by the Higher Institutions Centre of Excellence (HICoE) grant (Grant No.: 10-64-01-005) from the Ministry of Higher Education, Malaysia.

Compliance with ethical standards

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflict of interest.

Supplementary material

13105_2019_699_MOESM1_ESM.docx (1.9 mb)
ESM 1 (DOCX 1899 kb)
13105_2019_699_MOESM2_ESM.docx (87 kb)
ESM 2 (DOCX 86 kb)

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Copyright information

© University of Navarra 2019

Authors and Affiliations

  1. 1.Department Biochemistry & Molecular Medicine, Faculty of MedicineUniversiti Teknologi MARASungai BulohMalaysia
  2. 2.UKM Medical Molecular Biology Institute (UMBI)UKM Medical CenterKuala LumpurMalaysia
  3. 3.Department of Physiology, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
  4. 4.KPJ Ampang Putri HospitalAmpangMalaysia
  5. 5.Department of Biochemistry, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia

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