Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis

Growth Horm IGF Res. 2010 Feb;20(1):55-62. doi: 10.1016/j.ghir.2009.09.003. Epub 2009 Oct 22.

Abstract

The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines. Recently, potent anti-tumorigenic effects of pomegranate juice and extracts have been reported. Consequently, pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer, including prostate. In this study, we investigated the relationship between pomegranate-induced apoptosis in human prostate cancer cells and the IGF/IGFBP system. Treatment of LAPC4 prostate cancer cells with 10microg/ml POMx, a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content (37% punicalagins by HPLC), resulted in inhibition of cell proliferation and induction of apoptosis. Interestingly, co-treatment with POMx and IGFBP-3 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth. Western blot analysis revealed that treatment with POMx or POMx/IGFBP-3 combination resulted in increased JNK phosphorylation, and decreased Akt and mTOR activation, consistent with a growth inhibitory, pro-apoptotic function. We also investigated the relationship between IGF-1 and pomegranate-induced apoptosis in 22RV1 prostate cancer cells. Co-treatment with 100ng/ml IGF-1 completely blocked apoptosis induction by POMx. In contrast, IGF-I failed to inhibit POMx-induced apoptosis in R(-) cells, suggesting the importance of IGF-IR. POMx-treatment decreased Igf1 mRNA expression in a dose-dependent manner indicating that its actions also involve tumor-specific suppression of IGF-1. These studies revealed novel interactions between the IGF system and pomegranate-induced apoptosis.

Publication types

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

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Hydrolyzable Tannins / analysis
  • Hydrolyzable Tannins / pharmacology
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism*
  • Insulin-Like Growth Factor I / metabolism*
  • Intracellular Signaling Peptides and Proteins / drug effects
  • JNK Mitogen-Activated Protein Kinases / drug effects
  • Lythraceae / chemistry*
  • Male
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*
  • Prostatic Neoplasms / metabolism*
  • Protein-Serine-Threonine Kinases / drug effects
  • TOR Serine-Threonine Kinases

Substances

  • Antineoplastic Agents, Phytogenic
  • Hydrolyzable Tannins
  • Insulin-Like Growth Factor Binding Protein 3
  • Intracellular Signaling Peptides and Proteins
  • Plant Extracts
  • ellagitannin
  • Insulin-Like Growth Factor I
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases