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Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in

Alexandra M Fajardo1, Debra A MacKenzie1, Sarah L Olguin1

  • 1Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico, United States of America.

Plos One
|March 18, 2016
PubMed

Insights

Tocopherylquinone (TQ), an alpha-tocopherol oxidation product, potently inhibits prostate cancer cell growth and androgenic activity by down-regulating androgen receptors. Alpha-tocopherol (AT) showed no such effects, highlighting TQ's distinct therapeutic potential.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Alpha-tocopherol (AT) is a form of vitamin E with known biological functions.
  • Tocopherylquinone (TQ) is an oxidation product of AT with distinct properties.
  • Prostate cancer growth is often driven by androgen receptor (AR) signaling.

Purpose of the Study:

  • To compare the effects of AT and TQ on prostate cancer cell growth and androgenic activity.
  • To investigate the anti-androgenic mechanisms of TQ.
  • To determine if TQ's effects are distinct from AT.

Main Methods:

  • Cell culture of androgen-responsive (LAPC4, LNCaP) and androgen-independent (DU145) prostate cancer lines.
  • Reporter assays to measure androgen-induced activation.
  • Prostate-specific antigen (PSA) release assays.
  • Multifunctional Androgen Receptor Screening assay.
  • Quantitative gene expression analysis.
  • Western blotting for AR protein levels.
  • Antioxidant co-treatment experiments.

Main Results:

  • TQ significantly inhibited growth in androgen-responsive prostate cancer cells, but not androgen-independent cells.
  • TQ demonstrated potent anti-androgenic activity, inhibiting AR activation and PSA release.
  • TQ decreased expression of androgen-responsive genes (TM4SF1, KLK2, PSA) over 5-fold.
  • TQ down-regulated androgen receptor protein levels, an effect not seen with AT.
  • Antioxidants abrogated TQ-induced AR protein down-regulation.
  • AT did not affect androgenic endpoints or gene expression.

Conclusions:

  • Tocopherylquinone (TQ) exhibits distinct biological actions compared to alpha-tocopherol (AT).
  • TQ is a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer.
  • TQ's anti-androgenic effects are mediated by the down-regulation of androgen receptor protein.

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