Selective Growth Regulatory and Pro-Apoptotic Effects of DIM Is Mediated by AKT and NF-kappaB Pathways in Prostate Cancer Cells

Front Biosci. 2005 Jan 1;10:236-43. doi: 10.2741/1523. Print 2005 Jan 1.

Abstract

Prostate cancer is the second leading cause of cancer related deaths in men in the United States. I3C and its in vivo dimeric product, DIM, have been found to inhibit the growth of prostate cancer cells. However, the molecular mechanism(s) by which DIM elicits its effects on prostate cancer cells has not been fully elucidated. We have previously shown that I3C induces apoptosis and inhibits the activation of NF-kappaB pathway, which could be mediated via Akt signaling pathway. In this study, we investigated whether there is any cross-talk between Akt and NF-kappaB during DIM-induced apoptosis in PC-3 prostate cancer cells. We found that DIM inhibited cell growth and induced apoptosis in PC-3 prostate cancer cells but not in non-tumorigenic CRL2221 human prostate epithelial cells. DIM also inhibited EGFR expression, PI3K kinase activity, and Akt activation, and abrogated the EGF-induced activation of PI3K in prostate cancer cells. NF-kappaB DNA-binding analysis and transfection studies with Akt cDNA constructs revealed that Akt transfection resulted in the induction of NF-kappaB activity and this was inhibited by DIM treatment. DIM treatment also showed significant induction of apoptosis in non-transfected cells compared to Akt and Akt-Myr transfected prostate cancer cells. From these results, we conclude that the inhibition of Akt and NF-kappaB activity and their cross-talk is a novel mechanism by which DIM inhibits cell growth and induces apoptotic processes in prostate cancer cells but not in non-tumorigenic prostate epithelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Cell Line, Tumor
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Male
  • NF-kappa B / metabolism*
  • Prostatic Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Transfection

Substances

  • Indoles
  • NF-kappa B
  • indole-3-carbinol
  • Proto-Oncogene Proteins c-akt