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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital , New Taipei City, Taiwan.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan.
authors.forename: Sheng-Tsai
authors.initials: ST
authors.lastname: Lin
authors.affiliation: TMU Taipei Cancer Center, Taipei Medical University , Taipei, Taiwan.|Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan.|Breast Medical Center, Taipei Medical University Hospital , Taipei, Taiwan.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Tu
authors.affiliation: Department of Surgery, Mackay Memorial Hospital , Taipei, Taiwan.|Department of Medicine, Mackay Medical College , New Taipei City, Taiwan.|Nursing and Management, Mackay Junior College of Medicine , Taipei, Taiwan.
authors.forename: Po-Sheng
authors.initials: PS
authors.lastname: Yang
authors.affiliation: Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan.|Graduate Institue of Medical Sciences, College of Medicine, Taipei Medical University , Taipei, Taiwan.
authors.forename: Sung-Po
authors.initials: SP
authors.lastname: Hsu
authors.affiliation: Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan.|Department of Pathology, Taipei Medical University-Shuang Ho Hospital , Jhonghe City, Taiwan.
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Department of Food Science, Rutgers University , New Brunswick, New Jersey 08901, United States.
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan.|Department of Surgery, En Chu Kong Hospital , New Taipei City 237, Taiwan.
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital , New Taipei City, Taiwan.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Lai
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital , New Taipei City, Taiwan.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan.
authors.forename: Ming-Yao
authors.initials: MY
authors.lastname: Chen
authors.affiliation: TMU Taipei Cancer Center, Taipei Medical University , Taipei, Taiwan.|Breast Medical Center, Taipei Medical University Hospital , Taipei, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Chen
mesh_terms: D000368:Aged; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism*; D051559:Hepatocyte Nuclear Factor 6 / Q000378:metabolism; D006801:Humans; D008297:Male; D027845:Malus / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009367:Neoplasm Staging; D010693:Phloretin / Q000737:chemistry*; D059808:Polyphenols / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051273:Glucose Transporter Type 2; D051559:Hepatocyte Nuclear Factor 6; C496605:ONECUT1 protein, human; D059808:Polyphenols; D012333:RNA, Messenger; C495680:SLC2A2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005947:Glucose; D010693:Phloretin
keywords: apple polyphenol; colon cancer; glucose transporter 2; p53; phloretin