Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate-induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice

Jia Ching Wu, Mei Ling Tsai, Ching Shu Lai, Chih Yu Lo, Chi Tang Ho, Ying Jan Wang, Min Hsiung Pan

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental carcinogenic pollutants and they have become an important issue in food contamination. Dietary intake of PAHs has been recognized as a major route of human exposure. However, the mechanisms behind dietary PAH-induced colorectal cancer (CRC) remain unclear. Several studies have shown that polymethoxyflavones (PMFs) are effective in preventing carcinogen-induced CRC or colitis. In this study, we investigated the preventive effect of PMFs on benzo[a]pyrene/dextran sulfate sodium (BaP/DSS)-induced colorectal tumorigenesis in ICR mice. We found that PMFs significantly prevented BaP/DSS-induced colorectal tumor formation. BaP mutagenic metabolite and DNA adducts were found to be reduced in colonic tissue in the PMFs-treated groups through the modulation of BaP metabolism. At the molecular level, the results of RNA-sequencing indicated that PMFs ameliorated BaP/DSS-induced abnormal molecular mechanism change including activated inflammation, downregulated anti-oxidation targets, and induced metastasis genes. The autophagic defect caused by BaP/DSS-induced tumorigenesis was improved by pretreatment with PMFs. We found BaP/DSS-induced CRC may be a Wnt/β-catenin independent process. Additionally, consumption of PMFs extracts also altered the composition of gut microbiota and made it similar to that in the control group by increasing butyrate-producing probiotics and decreasing CRC-related bacteria. BaP in combination with DSS significantly induced colorectal tumorigenesis through induced DNA adduct formation, abnormal gene expression, and imbalanced gut microbiota composition. PMFs were a powerful preventive agent that suppressed BaP/DSS-induced CRC via modulating multiple pathways as well as ameliorating autophagic defect. These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1689-1701
Number of pages13
JournalInternational Journal of Cancer
Volume142
Issue number8
DOIs
StatePublished - Apr 15 2018

Fingerprint

Inbred ICR Mouse
Dextran Sulfate
Benzo(a)pyrene
Xenobiotics
Carcinogenesis
Colorectal Neoplasms
Polycyclic Aromatic Hydrocarbons
DNA Adducts
Food Contamination
RNA Sequence Analysis
Catenins
Environmental Pollutants
Butyrates
Probiotics
Colitis
Carcinogens
Down-Regulation
Neoplasm Metastasis
Inflammation
Bacteria

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

  • autophagic defect
  • colorectal cancer
  • microbiota
  • polycyclic aromatic hydrocarbons
  • polymethoxyflavones

Cite this

@article{4e8c24894fc04257bf488f24237ef8dc,
title = "Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate-induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice",
abstract = "Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental carcinogenic pollutants and they have become an important issue in food contamination. Dietary intake of PAHs has been recognized as a major route of human exposure. However, the mechanisms behind dietary PAH-induced colorectal cancer (CRC) remain unclear. Several studies have shown that polymethoxyflavones (PMFs) are effective in preventing carcinogen-induced CRC or colitis. In this study, we investigated the preventive effect of PMFs on benzo[a]pyrene/dextran sulfate sodium (BaP/DSS)-induced colorectal tumorigenesis in ICR mice. We found that PMFs significantly prevented BaP/DSS-induced colorectal tumor formation. BaP mutagenic metabolite and DNA adducts were found to be reduced in colonic tissue in the PMFs-treated groups through the modulation of BaP metabolism. At the molecular level, the results of RNA-sequencing indicated that PMFs ameliorated BaP/DSS-induced abnormal molecular mechanism change including activated inflammation, downregulated anti-oxidation targets, and induced metastasis genes. The autophagic defect caused by BaP/DSS-induced tumorigenesis was improved by pretreatment with PMFs. We found BaP/DSS-induced CRC may be a Wnt/β-catenin independent process. Additionally, consumption of PMFs extracts also altered the composition of gut microbiota and made it similar to that in the control group by increasing butyrate-producing probiotics and decreasing CRC-related bacteria. BaP in combination with DSS significantly induced colorectal tumorigenesis through induced DNA adduct formation, abnormal gene expression, and imbalanced gut microbiota composition. PMFs were a powerful preventive agent that suppressed BaP/DSS-induced CRC via modulating multiple pathways as well as ameliorating autophagic defect. These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis.",
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Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate-induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice. / Wu, Jia Ching; Tsai, Mei Ling; Lai, Ching Shu; Lo, Chih Yu; Ho, Chi Tang; Wang, Ying Jan; Pan, Min Hsiung.

In: International Journal of Cancer, Vol. 142, No. 8, 15.04.2018, p. 1689-1701.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate-induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice

AU - Wu, Jia Ching

AU - Tsai, Mei Ling

AU - Lai, Ching Shu

AU - Lo, Chih Yu

AU - Ho, Chi Tang

AU - Wang, Ying Jan

AU - Pan, Min Hsiung

PY - 2018/4/15

Y1 - 2018/4/15

N2 - Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental carcinogenic pollutants and they have become an important issue in food contamination. Dietary intake of PAHs has been recognized as a major route of human exposure. However, the mechanisms behind dietary PAH-induced colorectal cancer (CRC) remain unclear. Several studies have shown that polymethoxyflavones (PMFs) are effective in preventing carcinogen-induced CRC or colitis. In this study, we investigated the preventive effect of PMFs on benzo[a]pyrene/dextran sulfate sodium (BaP/DSS)-induced colorectal tumorigenesis in ICR mice. We found that PMFs significantly prevented BaP/DSS-induced colorectal tumor formation. BaP mutagenic metabolite and DNA adducts were found to be reduced in colonic tissue in the PMFs-treated groups through the modulation of BaP metabolism. At the molecular level, the results of RNA-sequencing indicated that PMFs ameliorated BaP/DSS-induced abnormal molecular mechanism change including activated inflammation, downregulated anti-oxidation targets, and induced metastasis genes. The autophagic defect caused by BaP/DSS-induced tumorigenesis was improved by pretreatment with PMFs. We found BaP/DSS-induced CRC may be a Wnt/β-catenin independent process. Additionally, consumption of PMFs extracts also altered the composition of gut microbiota and made it similar to that in the control group by increasing butyrate-producing probiotics and decreasing CRC-related bacteria. BaP in combination with DSS significantly induced colorectal tumorigenesis through induced DNA adduct formation, abnormal gene expression, and imbalanced gut microbiota composition. PMFs were a powerful preventive agent that suppressed BaP/DSS-induced CRC via modulating multiple pathways as well as ameliorating autophagic defect. These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis.

AB - Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental carcinogenic pollutants and they have become an important issue in food contamination. Dietary intake of PAHs has been recognized as a major route of human exposure. However, the mechanisms behind dietary PAH-induced colorectal cancer (CRC) remain unclear. Several studies have shown that polymethoxyflavones (PMFs) are effective in preventing carcinogen-induced CRC or colitis. In this study, we investigated the preventive effect of PMFs on benzo[a]pyrene/dextran sulfate sodium (BaP/DSS)-induced colorectal tumorigenesis in ICR mice. We found that PMFs significantly prevented BaP/DSS-induced colorectal tumor formation. BaP mutagenic metabolite and DNA adducts were found to be reduced in colonic tissue in the PMFs-treated groups through the modulation of BaP metabolism. At the molecular level, the results of RNA-sequencing indicated that PMFs ameliorated BaP/DSS-induced abnormal molecular mechanism change including activated inflammation, downregulated anti-oxidation targets, and induced metastasis genes. The autophagic defect caused by BaP/DSS-induced tumorigenesis was improved by pretreatment with PMFs. We found BaP/DSS-induced CRC may be a Wnt/β-catenin independent process. Additionally, consumption of PMFs extracts also altered the composition of gut microbiota and made it similar to that in the control group by increasing butyrate-producing probiotics and decreasing CRC-related bacteria. BaP in combination with DSS significantly induced colorectal tumorigenesis through induced DNA adduct formation, abnormal gene expression, and imbalanced gut microbiota composition. PMFs were a powerful preventive agent that suppressed BaP/DSS-induced CRC via modulating multiple pathways as well as ameliorating autophagic defect. These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis.

KW - autophagic defect

KW - colorectal cancer

KW - microbiota

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KW - polymethoxyflavones

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