Suppression of colorectal cancer cell growth by combined treatment of 6-gingerol and γ-tocotrienol via alteration of multiple signalling pathways

Khairunnisa’ Md Yusof, Suzana Makpol, Lye Siew Fen, A. Rahman A. Jamal, Wan Zurinah Wan Ngah

Research output: Contribution to journalArticle

Abstract

Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30–60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.

Original languageEnglish
JournalJournal of Natural Medicines
DOIs
Publication statusPublished - 1 Jan 2019

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Tocotrienols
Cell growth
Colorectal Neoplasms
Cells
Genes
RNA Sequence Analysis
Growth
Cell Cycle
Down-Regulation
RNA
Gene Expression
Wnt Signaling Pathway
Gene expression
Cytostatic Agents
Gene Expression Profiling
Regulator Genes
Caspases
DNA Repair
Chemical activation
Neoplasms

Keywords

  • 6-Gingerol (6G)
  • Cell death
  • Colon cancer
  • RNA sequencing
  • SW837 human colorectal cancer cells
  • γ-Tocotrienol (γT3)

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

Cite this

@article{f6002c1ddd5d40178047cd583f3a493f,
title = "Suppression of colorectal cancer cell growth by combined treatment of 6-gingerol and γ-tocotrienol via alteration of multiple signalling pathways",
abstract = "Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30–60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.",
keywords = "6-Gingerol (6G), Cell death, Colon cancer, RNA sequencing, SW837 human colorectal cancer cells, γ-Tocotrienol (γT3)",
author = "Yusof, {Khairunnisa’ Md} and Suzana Makpol and Fen, {Lye Siew} and {A. Jamal}, {A. Rahman} and {Wan Ngah}, {Wan Zurinah}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s11418-019-01323-6",
language = "English",
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TY - JOUR

T1 - Suppression of colorectal cancer cell growth by combined treatment of 6-gingerol and γ-tocotrienol via alteration of multiple signalling pathways

AU - Yusof, Khairunnisa’ Md

AU - Makpol, Suzana

AU - Fen, Lye Siew

AU - A. Jamal, A. Rahman

AU - Wan Ngah, Wan Zurinah

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30–60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.

AB - Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30–60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.

KW - 6-Gingerol (6G)

KW - Cell death

KW - Colon cancer

KW - RNA sequencing

KW - SW837 human colorectal cancer cells

KW - γ-Tocotrienol (γT3)

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U2 - 10.1007/s11418-019-01323-6

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JO - Natural Medicines

JF - Natural Medicines

SN - 1861-0293

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