Brassinin induces G1 phase arrest through increase of p21 and p27 by inhibition of the phosphatidylinositol 3-kinase signaling pathway in human colon cancer cells

Int J Oncol. 2012 Mar;40(3):816-24. doi: 10.3892/ijo.2011.1246. Epub 2011 Oct 27.

Abstract

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is activated in a broad spectrum of human cancers, including colon cancer. The natural product brassinin is a type of indole compound derived from cruciferous vegetables, and has been shown to have anti-proliferative effects against cancer for both in vivo and in vitro models. Here, we show for the first time that brassinin inhibits cell growth in human colon cancer cells by arresting the cell cycle at the G1 phase via inhibition of the PI3K signaling pathway. Brassinin increased the expression of p21 and p27, resulting in hypophosphorylation of the retinoblastoma gene (RB). Knockdown of p21 or p27 by each siRNA significantly repressed G1 phase arrest induced by brassinin. The increase of p21 and p27 was associated with inhibition of the PI3K signaling pathway. In addition, exogenous expression of constitutively active Akt represses the cell cycle arrest at G1 phase induced by brassinin. These results suggest the possibility that brassinin inhibits the PI3K signaling pathway and upregulates the expression of p21 and p27, thereby inducing G1 phase arrest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / drug effects*
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
  • G1 Phase / drug effects*
  • G1 Phase / genetics
  • HT29 Cells
  • Humans
  • Indoles / pharmacology*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • Retinoblastoma Protein / genetics
  • Signal Transduction / drug effects
  • Thiocarbamates / pharmacology*
  • Up-Regulation / drug effects

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Indoles
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Messenger
  • Retinoblastoma Protein
  • Thiocarbamates
  • brassinin
  • Cyclin-Dependent Kinase Inhibitor p27
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt