Indole-3-carbinol (I3C) Induced Cell Growth Inhibition, G1 Cell Cycle Arrest and Apoptosis in Prostate Cancer Cells

Oncogene. 2001 May 24;20(23):2927-36. doi: 10.1038/sj.onc.1204365.

Abstract

Prostate cancer is one of the most common cancers in men and it is the second leading cause of cancer related death in men in the United States. Recent dietary and epidemiological studies have suggested the benefit of dietary intake of fruits and vegetables in lowering the incidence of prostate cancer. A diet rich in fruits and vegetables provides phytochemicals, particularly indole-3-carbinol (I3C), which may be responsible for the prevention of many types of cancer, including hormone-related cancers such as prostate. Studies to elucidate the role and the molecular mechanism(s) of action of I3C in prostate cancer, however, have not been conducted. In the current study, we investigated whether I3C had any effect against prostate cancer cells and, if so, attempts were made to identify the potential molecular mechanism(s) by which I3C elicits its biological effects on prostate cancer cells. Here we report for the first time that I3C inhibits the growth of PC-3 prostate cancer cells. Induction of G1 cell cycle arrest was also observed in PC-3 cells treated with I3C, which may be due to the observed effects of I3C in the up-regulation of p21(WAF1) and p27(Kip1) CDK inhibitors, followed by their association with cyclin D1 and E and down-regulation of CDK6 protein kinase levels and activity. The induction of p21(WAF1) appears to be transcriptionally upregulated and independent of the p53 responsive element. In addition, I3C inhibited the hyperpohosphorylation of the Retinoblastoma (Rb) protein in PC-3 cells. Induction of apoptosis was also observed in this cell line when treated with I3C, as measured by DNA laddering and poly (ADP-ribose) polymersae (PARP) cleavage. We also found an up-regulation of Bax, and down-regulation of Bcl-2 in I3C-treated cells. These effects may also be mediated by the down-regulation of NF-kappaB observed in I3C treated PC-3 cells. From these results, we conclude that I3C inhibits the growth of PC-3 prostate cancer cells by inducing G1 cell cycle arrest leading to apoptosis, and regulates the expression of apoptosis-related genes. These findings suggest that I3C may be an effective chemopreventive or therapeutic agent against prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Cycle Proteins*
  • Cell Division / drug effects
  • Cyclin D1 / drug effects
  • Cyclin D1 / metabolism
  • Cyclin E / drug effects
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases*
  • Cyclins / drug effects
  • Cyclins / metabolism
  • Down-Regulation
  • G1 Phase / drug effects*
  • Humans
  • Indoles / pharmacology*
  • Male
  • Microtubule-Associated Proteins / drug effects
  • Microtubule-Associated Proteins / metabolism
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Phosphorylation
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology*
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Retinoblastoma Protein / drug effects
  • Retinoblastoma Protein / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / drug effects
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins*
  • bcl-2-Associated X Protein

Substances

  • Anticarcinogenic Agents
  • BAX protein, human
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Indoles
  • Microtubule-Associated Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • bcl-2-Associated X Protein
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • indole-3-carbinol
  • Protein-Serine-Threonine Kinases
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases