Pro-Apoptotic Effect of Grape Seed Extract on MCF-7 Involves Transient Increase of Gap Junction Intercellular Communication and Cx43 Up-Regulation: A Mechanism of Chemoprevention

Int J Mol Sci. 2019 Jul 2;20(13):3244. doi: 10.3390/ijms20133244.


Growing evidence suggests dietary antioxidants reduce the risk of several cancers. Grape seeds extracts (GSE) are a rich source of polyphenols known to have antioxidant, chemopreventive and anticancer properties. Herein, we investigated the in vitro effects and putative action mechanisms of a grape seed extract (GSE) on human breast cancer cells (MCF-7). The effects of GSE were evaluated on cell proliferation, apoptosis and gap-junction-mediated cell-cell communications (GJIC), as basal mechanism involved in the promotion stage of carcinogenesis. GSE (0.05-100 μg/mL) caused a significant dose- and time-dependent inhibition of MCF-7 viability and induced apoptotic cell death, as detected by Annexin-V/Propidium Iodide. Concurrently, GSE induced transient but significant enhancement of GJIC in non-communicating MCF-7 cells, as demonstrated by the scrape-loading/dye-transfer (SL/DT) assay and an early and dose-dependent re-localization of the connexin-43 (Cx43) proteins on plasma membranes, as assayed by immunocytochemistry. Finally, real-time-PCR has evidenced a significant increase in cx43 mRNA expression. The results support the hypothesis that the proliferation inhibition and pro-apoptotic effect of GSE against this breast cancer cell model are mediated by the GJIC improvement via re-localization of Cx43 proteins and up-regulation of cx43 gene, and provide further insight into the action mechanisms underlying the health-promoting action of dietary components.

Keywords: Cx43 expression; MCF-7; antioxidants; apoptosis; chemoprevention; chemotherapy; connexins; gap junction intercellular communication; grape seed Extract (GSE); nutraceuticals.

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / prevention & control*
  • Cell Communication / drug effects
  • Connexin 43 / genetics
  • Connexin 43 / metabolism
  • Female
  • Gap Junctions / drug effects
  • Gap Junctions / metabolism
  • Grape Seed Extract / pharmacology*
  • Humans
  • MCF-7 Cells
  • Up-Regulation / drug effects


  • Anticarcinogenic Agents
  • Antioxidants
  • Connexin 43
  • GJA1 protein, human
  • Grape Seed Extract