Oridonin induces G2/M arrest and apoptosis via activating ERK-p53 apoptotic pathway and inhibiting PTK-Ras-Raf-JNK survival pathway in murine fibrosarcoma L929 cells

Arch Biochem Biophys. 2009 Oct 1;490(1):70-5. doi: 10.1016/j.abb.2009.08.011. Epub 2009 Aug 20.

Abstract

Oridonin was reported to induce L929 cell apoptosis via ROS-mediated mitochondrial and ERK pathways; however, the precise mechanisms by which oridonin induces cell death remain unclear. Herein, we found that oridonin treatment induced an increase in G(2)/M phase cell percentage. And, G(2)/M phase arrest was associated with down-regulation of cell cycle related cdc2, cdc25c and cyclinB levels, as well as up-regulation of p21 and p-cdc2 levels. In addition, we discovered that interruption of p53 activation decreased oridonin-induced apoptosis, and blocking ERK by specific inhibitors or siRNA suppressed oridonin-induced p53 activation. Moreover, inhibition of PTK, protein kinase C, Ras, Raf or JNK activation increased oridonin-induced apoptosis. Also, the level of Ras, Raf or JNK was down-regulated by oridonin, and the inhibition of PTK, Ras, Raf activation decreased p-JNK level. In conclusion, oridonin induces L929 cell G(2)/M arrest and apoptosis, which is regulated by promoting ERK-p53 apoptotic pathway and suppressing PTK-mediated survival pathway.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Diterpenes, Kaurane / pharmacology*
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Fibrosarcoma / genetics
  • Fibrosarcoma / metabolism*
  • G2 Phase / drug effects*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mice
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors
  • RNA, Small Interfering / metabolism
  • Time Factors
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • ras Proteins / antagonists & inhibitors

Substances

  • Antineoplastic Agents, Phytogenic
  • Diterpenes, Kaurane
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • oridonin
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-raf
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • ras Proteins