Artepillin C Inhibits Cell Proliferation by Cell Cycle Arrest at G0/G1 Phase Accompanied by Up-Regulation of p27Kip1 in Human Hepatoma HepG2 Cells
Takashi Hashimoto *
Division of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan.
Weitao Shang
Department of Biofunctional Chemistry, Graduate School of Science and Technology, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan.
Kazuki Kanazawa
Division of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan and Department of Biofunctional Chemistry, Graduate School of Science and Technology, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan.
*Author to whom correspondence should be addressed.
Abstract
Artepillin C, 3, 5-diprenyl-4-hydroxycinnamic acid, is one of the bioactive constituents in Brazilian propolis. In the present study, the anticarcinogenic activity of this compound was investigated in human hepatoma HepG2 cells. Artepillin C inhibited the cell proliferation in a dose- and time-dependent manner accompanied by G0/G1 phase arrest in the cell cycle. This compound caused a decrease in the phosphorylation levels of the retinoblastoma protein at Ser780 and Ser807/811 and a decrease in the kinase activity of the cyclinD and CDK4 complex without any change in these protein levels. Artepillin C increased the protein level of p27Kip1, known as a CDK inhibitor. This up-regulation was regulated by both the transcriptional and post-transcriptional levels, i.e., the treatment increased the mRNA of p27Kip1 and decreased the proteosome activity. Thus, artepillin C induces cell cycle arrest at G0/G1 phase accompanied by up-regulation of p27Kip1, resulting in the inhibition of cell proliferation in HepG2 cells. This study suggested that artepillin C will be a promising anti-cancer agent against hepatoma cancer.
Keywords: Artepilinn C, Cell cycle arrest, G0/G1 phase, HepG2 cells, p27Kip1, Propolis