Apple Polyphenol Phloretin Inhibits Colorectal Cancer Cell Growth via Inhibition of the Type 2 Glucose Transporter and Activation of p53-Mediated Signaling

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Abstract

Glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells. The average GLUT2 mRNA level in 12 of 27 (44.4%) cases was 2.4-fold higher in tumor compared to normal tissues (∗, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95% CI = 9.22-26.54-fold;∗, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0-100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0-100 μM, for 24 h). The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness.

Original languageEnglish
Pages (from-to)6826-6837
Number of pages12
JournalJournal of Agricultural and Food Chemistry
Volume64
Issue number36
DOIs
Publication statusPublished - Sep 14 2016

Fingerprint

Glucose Transporter Type 2
Phloretin
glucose transporters
Cell growth
Malus
Polyphenols
colorectal neoplasms
growth retardation
Tumors
cell growth
Colorectal Neoplasms
polyphenols
apples
Chemical activation
neoplasms
Growth
Facilitative Glucose Transport Proteins
Neoplasms
Messenger RNA
Hepatocyte Nuclear Factor 6

Keywords

  • apple polyphenol
  • colon cancer
  • glucose transporter 2
  • p53
  • phloretin

ASJC Scopus subject areas

  • Chemistry(all)
  • Agricultural and Biological Sciences(all)

Cite this

@article{f99abced3c754c3884b0d1e4527a1bb1,
title = "Apple Polyphenol Phloretin Inhibits Colorectal Cancer Cell Growth via Inhibition of the Type 2 Glucose Transporter and Activation of p53-Mediated Signaling",
abstract = "Glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells. The average GLUT2 mRNA level in 12 of 27 (44.4{\%}) cases was 2.4-fold higher in tumor compared to normal tissues (∗, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95{\%} CI = 9.22-26.54-fold;∗, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0-100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0-100 μM, for 24 h). The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness.",
keywords = "apple polyphenol, colon cancer, glucose transporter 2, p53, phloretin",
author = "Lin, {Sheng Tsai} and Tu, {Shih Hsin} and Yang, {Po Sheng} and Hsu, {Sung Po} and Lee, {Wei Hwa} and Ho, {Chi Tang} and Wu, {Chih Hsiung} and Lai, {Yu Hsin} and Chen, {Ming Yao} and Chen, {Li Ching}",
year = "2016",
month = "9",
day = "14",
doi = "10.1021/acs.jafc.6b02861",
language = "English",
volume = "64",
pages = "6826--6837",
journal = "Journal of Agricultural and Food Chemistry",
issn = "0021-8561",
publisher = "American Chemical Society",
number = "36",

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TY - JOUR

T1 - Apple Polyphenol Phloretin Inhibits Colorectal Cancer Cell Growth via Inhibition of the Type 2 Glucose Transporter and Activation of p53-Mediated Signaling

AU - Lin, Sheng Tsai

AU - Tu, Shih Hsin

AU - Yang, Po Sheng

AU - Hsu, Sung Po

AU - Lee, Wei Hwa

AU - Ho, Chi Tang

AU - Wu, Chih Hsiung

AU - Lai, Yu Hsin

AU - Chen, Ming Yao

AU - Chen, Li Ching

PY - 2016/9/14

Y1 - 2016/9/14

N2 - Glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells. The average GLUT2 mRNA level in 12 of 27 (44.4%) cases was 2.4-fold higher in tumor compared to normal tissues (∗, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95% CI = 9.22-26.54-fold;∗, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0-100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0-100 μM, for 24 h). The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness.

AB - Glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells. The average GLUT2 mRNA level in 12 of 27 (44.4%) cases was 2.4-fold higher in tumor compared to normal tissues (∗, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95% CI = 9.22-26.54-fold;∗, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0-100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0-100 μM, for 24 h). The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness.

KW - apple polyphenol

KW - colon cancer

KW - glucose transporter 2

KW - p53

KW - phloretin

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U2 - 10.1021/acs.jafc.6b02861

DO - 10.1021/acs.jafc.6b02861

M3 - Article

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VL - 64

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JO - Journal of Agricultural and Food Chemistry

JF - Journal of Agricultural and Food Chemistry

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