Ellagic Acid Exerts Anti-proliferation Effects via Modulation of Tgf-Β/Smad3 Signaling in MCF-7 Breast Cancer Cells

  • Zhang, Tao (The Fourth Affiliated Hospital of Harbin Medical University) ;
  • Chen, Hong-Sheng (The Fourth Affiliated Hospital of Harbin Medical University) ;
  • Wang, Li-Feng (Xin Hua Hospital Affiliated to Shang Hai Jiao Tong University School of Medicine) ;
  • Bai, Ming-Han (The Fourth Affiliated Hospital of Harbin Medical University) ;
  • Wang, Yi-Chong (The Fourth Affiliated Hospital of Harbin Medical University) ;
  • Jiang, Xiao-Feng (The Fourth Affiliated Hospital of Harbin Medical University) ;
  • Liu, Ming (The Fourth Affiliated Hospital of Harbin Medical University)
  • Published : 2014.01.15


Ellagic acid has been shown to inhibit tumor cell growth. However, the underlying molecular mechanisms remain elusive. In this study, our aim was to investigate whether ellagic acid inhibits the proliferation of MCF-7 human breast cancer cells via regulation of the TGF-${\beta}$/Smad3 signaling pathway. MCF-7 breast cancer cells were transfected with pEGFP-C3 or pEGFP-C3/Smad3 plasmids, and treated with ellagic acid alone or in combination with SIS3, a specific inhibitor of Smad3 phosphorylation. Cell proliferation was assessed by MTT assay and the cell cycle was detected by flow cytometry. Moreover, gene expression was detected by RT-PCR, real-time PCR and Western blot analysis. The MTT assay showed that SIS3 attenuated the inhibitory activity of ellagic acid on the proliferation of MCF-7 cells. Flow cytometry revealed that ellagic acid induced G0/G1 cell cycle arrest which was mitigated by SIS3. Moreover, SIS3 reversed the effects of ellagic acid on the expression of downstream targets of the TGF-${\beta}$/Smad3 pathway. In conclusion, ellagic acid leads to decreased phosphorylation of RB proteins mainly through modulation of the TGF-${\beta}$/Smad3 pathway, and thereby inhibits the proliferation of MCF-7 breast cancer cells.


  1. Adams LS, Phung S, Yee N, et al (2010). Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway. Cancer Res, 70, 3594-605.
  2. Chen HS, Liu M, Shi LJ, et al (2011). Effects of raspberry phytochemical extract on cell proliferation, apoptosis, and serum proteomics in a rat model. J Food Sci, 76, T192-8.
  3. Derynck R, Zhang YE (2003). Smad-dependent and Smadindependent pathways in TGF-${\beta}$ family signaling. Nature, 425, 577-84.
  4. Jinnin M, Ihn H, Tamaki K (2006). Characterization of SIS3, a Novel Specific Inhibitor of Smad3, and Its Effect on Transforming Growth Factor-1-Induced Extracellular Matrix Expression. Mol Pharmacol, 69, 597-607.
  5. Leaslc A, Abraham DJ (2004). TGF-${\beta}$ signaling and the fihrotic response. FASEB J, 18, 816-27.
  6. Li TM, Chen GW, Su CC, et al (2005). Ellagic acid induced p53/ p21 expression, G1 arrest and apoptosis in human bladder cancer T24 cells. Anticancer Res, 25, 971-9.
  7. Maiti B, Li J, de Bruin A, Gordon F J, et al (2005). Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem, 280, 18211-20.
  8. Muller H, Moroni MC, Vigo E, et al (1997). Induction of S-phase entry by E2F transcription factors depends on their nuclear localization. Mol Cell Biol, 17, 5508-20.
  9. Narayanan BA, Re GG (2001). IGF-II down regulation associated cell cycle arrest in colon cancer cells exposed to phenolic antioxidant ellagic acid. Anticancer Res, 21, 359-64.
  10. Su E, Han X, Jiang G (2010). The transforming growth factor beta 1-SMAD signaling pathway involved in human chronic myeloid leukemia. Tumor, 96, 659-66.
  11. Tian F, DaCosta Byfield S, et al (2003). Reduction in Smad2/3Signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res, 63, 8284-A92.
  12. Xu Y, Pasche B (2007). TGF-${\beta}$ signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet, 16, R14-R20.
  13. Yu B, Lane ME, Wadler S (2002). SU9516, a cyclin-dependent kinase 2 inhibitor, promotes accumulation of high molecular weight E2F complexes in human colon carcinoma cells. Biochem Pharmacol, 64, 1091-100.

Cited by

  1. L. Cork Extracts Induce Apoptosis in Human Myeloid Leukaemia HL-60 Cells vol.29, pp.8, 2015,
  2. Apoptotic efficacy of biogenic silver nanoparticles on human breast cancer MCF-7 cell lines vol.4, pp.2-4, 2015,
  3. Pomegranate Extract Improves Menopausal Syndrome in Ovariectomized Rats vol.44, pp.4, 2015,
  4. Direct inhibition of ACTN4 by ellagic acid limits breast cancer metastasis via regulation of β-catenin stabilization in cancer stem cells vol.36, pp.1, 2017,
  5. Multiple effects of ellagic acid on human colorectal carcinoma cells identified by gene expression profile analysis vol.50, pp.2, 2017,
  6. Leaf and Root Extracts from Campomanesia adamantium (Myrtaceae) Promote Apoptotic Death of Leukemic Cells via Activation of Intracellular Calcium and Caspase-3 vol.8, pp.1663-9812, 2017,
  7. Gallnuts: A Potential Treasure in Anticancer Drug Discovery vol.2018, pp.1741-4288, 2018,
  8. Experimental Evidence of the Antitumor, Antimetastatic and Antiangiogenic Activity of Ellagic Acid vol.10, pp.11, 2018,
  9. Ellagic acid, sulforaphane, and ursolic acid in the prevention and therapy of breast cancer: current evidence and future perspectives vol.25, pp.5, 2018,
  10. root extract on HYBID (KIAA1199)-mediated hyaluronan degradation and skin wrinkling vol.41, pp.1, 2019,