The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter

Kuan-Hsun Wu ^a,b,c, Chi-Tang Ho ^d, Zhao-Feng Chen ^e, Li-Ching Chen ^f,g,h,i, Jacqueline Whang-Peng ^f,i, Teng-Nan Lin ^j,**, Yuan-Soon Ho ^e,f,k,l,*

^a The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan

^b Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

^c Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

^d Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA

^e Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

^f Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan

^g Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan

^h Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

ⁱ Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

^j Institute of Biomedical Sciences, Academia Sinica, Taiwan

^k School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

^l Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan

Human triple-negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer. Glucose transporters (GLUTs) are required for glucose uptake in malignant cancer cells and are ideal targets for cancer therapy. To determine whether the inhibition of GLUTs could be used in TNBC cell therapy, the apple polyphenol phloretin (Ph) was used as a specific antagonist of GLUT2 protein function in human TNBC cells. Interestingly, we found that Ph (10–150 μM, for 24 h) inhibited cell growth and arrested the cell cycle in MDA-MB-231 cells in a p53 mutant-dependent manner, which was confirmed by pre-treatment of the cells with a p53-specific dominant-negative expression vector. We also found that Ph treatment (10–150 μM, for 24 h) significantly decreased the migratory activity of the MDA-MB-231 cells through the inhibition of paxillin/FAK, Src, and alpha smooth muscle actin (α-sMA) and through the activation of E-cadherin. Furthermore, the anti-tumorigenic effect of Ph (10, 50 mg/kg or DMSO twice a week for six weeks) was demonstrated in vivo using BALB/c nude mice bearing MDA-MB-231 tumor xenografts. A decrease in N-cadherin, vimentin and an increase in p53, p21 and E-cadherin were detected in the tumor tissues. In conclusion, inhibition of GLUT2 by the apple polyphenol Ph could potentially suppress TNBC tumor cell growth and metastasis.

Keywords: Apple polyphenol, Breast cancer, Glucose transporter 2, Phloretin, Triple-negative breast cancer