Rosmarinic Acid, a Component of Rosemary Tea, Induced the Cell Cycle Arrest and Apoptosis through Modulation of HDAC2 Expression in Prostate Cancer Cell Lines

Nutrients. 2018 Nov 16;10(11):1784. doi: 10.3390/nu10111784.

Abstract

Rosmarinic acid (RA), a main phenolic compound contained in rosemary which is used as tea, oil, medicine and so on, has been known to present anti-inflammatory, anti-oxidant and anti-cancer effects. Histone deacetylases (HDACs) are enzymes that play important roles in gene expression by removing the acetyl group from histone. The aberrant expression of HDAC in human tumors is related with the onset of human cancer. Especially, HDAC2, which belongs to HDAC class I composed of HDAC 1, 2, 3 and 8, has been reported to be highly expressed in prostate cancer (PCa) where it downregulates the expression of p53, resulting in an inhibition of apoptosis. The purpose of this study is to investigate the effect of RA in comparison with suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor used as an anti-cancer agent, on survival and apoptosis of PCa cell lines, PC-3 and DU145, and the expression of HDAC. RA decreased the cell proliferation in cell viability assay, and inhibited the colony formation and tumor spheroid formation. Additionally, RA induced early- and late-stage apoptosis of PC-3 and DU145 cells in Annexin V assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. In western blot analysis, RA inhibited the expression of HDAC2, as SAHA did. Proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E1 were downregulated by RA, whereas p21 was upregulated. In addition, RA modulated the protein expression of intrinsic mitochondrial apoptotic pathway-related genes, such as Bax, Bcl-2, caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) (cleaved) via the upregulation of p53 derived from HDAC2 downregulation, leading to the increased apoptosis of PC-3 and DU145 cells. Taken together, treatment of RA to PCa cell lines inhibits the cell survival and induces cell apoptosis, and it can be used as a novel therapeutic agent toward PCa.

Keywords: Rosmarinic acid; cell cycle arrest and apoptosis; histone deacetylase 2 (HDAC2); p53; suberoylanilide hydroxamic acid (SAHA).

MeSH terms

  • Annexin A5
  • Apoptosis / drug effects*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Cycle Checkpoints / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cinnamates / analysis*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • DNA Fragmentation / drug effects
  • Depsides / analysis*
  • Gene Expression Regulation
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism
  • Prostatic Neoplasms / metabolism
  • Rosmarinus / chemistry*
  • Signal Transduction
  • Teas, Herbal
  • Teas, Medicinal
  • Vorinostat / analysis
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • Annexin A5
  • BAX protein, human
  • CCND1 protein, human
  • CCNE1 protein, human
  • Cinnamates
  • Cyclin E
  • Depsides
  • Histone Deacetylase Inhibitors
  • Oncogene Proteins
  • PCNA protein, human
  • Proliferating Cell Nuclear Antigen
  • Teas, Herbal
  • bcl-2-Associated X Protein
  • Cyclin D1
  • Vorinostat
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • CASP3 protein, human
  • Caspase 3
  • HDAC2 protein, human
  • Histone Deacetylase 2
  • Histone Deacetylases
  • rosmarinic acid