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Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

Joo Hyoung Lee1, Tatyana Isayeva1, Matthew R Larson2

  • 1Departments of Pathology and.

Proceedings of the National Academy of Sciences of the United States of America
|January 22, 2015
PubMed

Insights

Endostatin effectively inhibits castration-resistant prostate cancer (CRPC) by directly interacting with the androgen receptor (AR). This novel mechanism reduces AR levels and gene transcription, offering new therapeutic strategies for CRPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Castration-resistant prostate cancer (CRPC) poses a significant clinical challenge due to acquired resistance to androgen receptor (AR)-targeted therapies.
  • Novel therapeutic strategies are urgently needed to overcome treatment resistance in CRPC.

Purpose of the Study:

  • To investigate the novel anti-cancer effects of endostatin in prostate cancer cells.
  • To elucidate the molecular mechanisms by which endostatin impacts androgen receptor (AR) signaling and function.

Main Methods:

  • Utilized structural modeling and functional analyses to investigate endostatin's interaction with the androgen receptor (AR).
  • Assessed endostatin's effects on intracellular trafficking, nuclear AR levels, and AR-target gene transcription in prostate cancer cells.

Main Results:

  • Endostatin efficiently trafficked into prostate cancer cells and directly interacted with the androgen receptor (AR).
  • Endostatin reduced nuclear AR levels and down-regulated AR-target gene transcription.
  • A phenylalanine-rich α1-helix in endostatin was identified to antagonize AR transcriptional activity by interacting with AR's activation function (AF)-2 and N-terminal AF-1 domains.

Conclusions:

  • Endostatin acts as an endogenous AR inhibitor, impairing AR function through protein-protein interactions.
  • Endostatin's antitumor effects extend beyond angiogenesis inhibition to suppressing AR-mediated disease progression in CRPC.
  • These findings highlight endostatin as a potential therapeutic agent for CRPC by targeting AR signaling.
Keywords:
androgen receptorchemoresistanceendostatinprostate cancer

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