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1,1-bis(3 '-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways | Academic Article individual record

1,1-Bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu) is a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, and treatment of SKOV3 ovarian cancer cells with this compound (5 micromol/L) inhibits cell proliferation, whereas up to 15 micromol/L rosiglitazone had no effect on cell growth. DIM-C-pPhtBu also inhibits G0-G1 to S phase cell cycle progression and this is linked, in part, to PPARgamma-dependent induction of the cyclin-dependent kinase inhibitor p21. DIM-C-pPhtBu induces PPARgamma-independent down-regulation of cyclin D1 and we therefore further investigated activation of receptor-independent pathways. DIM-C-pPhtBu also induced apoptosis in SKOV3 cells and this was related to induction of glucose-related protein 78, which is typically up-regulated as part of the unfolded protein response during endoplasmic reticulum (ER) stress. Activation of ER stress was also observed in other ovarian cancer cell lines treated with DIM-C-pPhtBu. In addition, DIM-C-pPhtBu induced CCAAT/enhancer binding protein homologous protein through both ER stress and c-jun NH2-terminal kinase-dependent pathways, and CCAAT/enhancer binding protein homologous protein activated death receptor 5 and the extrinsic pathway of apoptosis. These results show that DIM-C-pPhtBu inhibits growth and induces apoptosis in ovarian cancer cells through both PPARgamma-dependent and PPARgamma-independent pathways, and this complex mechanism of action will be advantageous for future clinical development of these compounds for treatment of ovarian cancer.

author list (cited authors)
Lei, P., Abdelrahim, M., & Safe, S.
publication date
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  • Rabbits
  • Cell Cycle
  • Endoplasmic Reticulum
  • Indoles
  • Transcription Factor Chop
  • Apoptosis
  • PPAR Gamma
  • Animals
  • JNK Mitogen-Activated Protein Kinases
  • Cyclin D1
  • Protein-Serine-Threonine Kinases
  • Female
  • Down-Regulation
  • Receptors, Tnf-related Apoptosis-inducing Ligand
  • P21-Activated Kinases
  • Humans
  • Cell Growth Processes
  • Ovarian Neoplasms