Dietary Pterostilbene Is a Novel MTA1-targeted Chemopreventive and Therapeutic Agent in Prostate Cancer

Oncotarget. 2016 Apr 5;7(14):18469-84. doi: 10.18632/oncotarget.7841.

Abstract

Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1- targeted chemopreventive and therapeutic efficacy of pterostilbene, a natural potent analog of resveratrol, in pre-clinical models of prostate cancer. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. Loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis. This restrained prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice and reduced tumor development and progression in prostate-specific Pten-null mice. Our findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. More significantly, it offers pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.

Keywords: MTA1; chemoprevention; prostate cancer; pterostilbene; therapy.

Publication types

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

MeSH terms

  • Animals
  • Chemoprevention
  • Histone Deacetylases / biosynthesis*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / prevention & control*
  • Random Allocation
  • Repressor Proteins / biosynthesis*
  • Stilbenes / pharmacology*
  • Transcription Factors / biosynthesis*

Substances

  • Mta1 protein, human
  • Mta1 protein, mouse
  • Repressor Proteins
  • Stilbenes
  • Transcription Factors
  • pterostilbene
  • Histone Deacetylases