Inhibition of mTOR signaling by oleanolic acid contributes to its anti-tumor activity in osteosarcoma cells

J Orthop Res. 2011 Jun;29(6):846-52. doi: 10.1002/jor.21311. Epub 2011 Jan 18.

Abstract

Oleanolic acid (OA), a pentacyclic triterpenoid exhibits potent anti-tumor activity against many tumor cell lines. But the mechanisms through which OA inhibits osteosarcoma cells are not known. The mammalian target of rapamycin (mTOR) serves as a central regulator of cell growth, proliferation, survival, and metabolism by integrating intracellular and extracellular signals. In this study, we examined effects of OA on proliferation, cell cycle progression, apoptosis in osteosarcoma cells, and involvement of mTOR signaling in this process. OA inhibited cell proliferation and colony formation, induced G1 arrest in osteosarcoma MG63 and Saos-2 cells dose and time dependently. The protein level of cyclin D1, which plays critical role in G1 to S phase transition and servers as a downstream target of mTOR complex 1 (mTORC1) was down-regulated by OA. Phosphorylation of p70 ribosomal S6 kinase 1 (p70 S6K1) (T389) and S6 (S235/236), mediators of mTORC1 signaling in controlling protein translation and cell growth, was also inhibited by OA. Furthermore, OA inhibited phosphorylation of Akt, a pro-survival factor and substrate for mTORC2. Inactivation of Akt correlated with pro-apoptotic role of OA in osteosarcoma cells, as manifested by an increase in annexin V-FITC binding, cleavage of poly (ADP-ribose) polymerase (PARP) and activation of caspases 3. Our results suggest that OA is a promising agent for treatment of osteosarcoma and mTOR signaling may contribute to its anti-tumor effects on osteosarcoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Drugs, Chinese Herbal / pharmacology
  • Drugs, Chinese Herbal / therapeutic use*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes
  • Oleanolic Acid / pharmacology
  • Oleanolic Acid / therapeutic use*
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / metabolism
  • Proteins / antagonists & inhibitors
  • Proteins / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism

Substances

  • CRTC2 protein, human
  • Drugs, Chinese Herbal
  • Multiprotein Complexes
  • Proteins
  • Transcription Factors
  • Oleanolic Acid
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1