Biphasic regulation of spindle assembly checkpoint by low and high concentrations of resveratrol leads to the opposite effect on chromosomal instability

Mutat Res Genet Toxicol Environ Mutagen. 2018 Jan;825:19-30. doi: 10.1016/j.mrgentox.2017.11.004. Epub 2017 Nov 8.


Resveratrol (RSV) is a naturally occurring polyphenolic phytoalexin possessing numerous health-promoting effects. Chromosomal instability (CIN), usually results from defective spindle assembly checkpoint (SAC), is a major contributor to many diseases. While it's recently recognized that RSV exhibits a nonlinear dose response for disease prevention, whether it's the case for its role in CIN remains unknown. Here, we investigated the potential of a broad range of RSV concentrations (0.01-100μM) on CIN and the underlying mechanisms in human normal colon epithelial NCM460 cells. CIN was measured by cytokinesis-block micronucleus assay; mitotic fidelity was determined by aberrant mitosis analysis; SAC activity was assessed by nocodazole-challenge assay, and the expression of SAC genes was examined by RT-qPCR. We found that 0.1μM RSV significantly reduced CIN (P<0.01), while 100μM RSV significantly induced it (P<0.05). Mitotic infidelity was significantly prevented by 0.1μM RSV but promoted by 100μM RSV (P<0.05 for both). Moreover, the function of SAC was sustained and impaired by 0.1μM and 100μM RSV, respectively. Several SAC genes, including Aurora-B, Aurora-C, Plk-1 and CENP-E, were significantly up-regulated and down-regulated by 0.1μM and 100μM RSV, respectively (P<0.05). In conclusion, RSV exhibited a biphasic dose-dependent effect on CIN that was exerted via the regulation of mitotic fidelity through the SAC network. The health implications of these findings were summarized.

Keywords: Chromosomal instability; Hormesis; Human colon cells; Mitotic aberrations; Resveratrol; Spindle assembly checkpoint.

MeSH terms

  • Aurora Kinase B / genetics
  • Aurora Kinase C / genetics
  • Cell Cycle Proteins / genetics
  • Cell Line
  • Chromosomal Instability
  • Chromosomal Proteins, Non-Histone / genetics
  • Colon / cytology*
  • Colon / drug effects
  • Colon / metabolism
  • Dose-Response Relationship, Drug
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects*
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / genetics
  • Resveratrol / toxicity*


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Proto-Oncogene Proteins
  • centromere protein E
  • AURKB protein, human
  • AURKC protein, human
  • Aurora Kinase B
  • Aurora Kinase C
  • Protein Serine-Threonine Kinases
  • polo-like kinase 1
  • Resveratrol