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Maintenance of androgen receptor inactivation by S-nitrosylation

Yu Qin1, Anindya Dey, Hamsa Thayele Purayil

  • 1Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida.

Cancer Research
|October 15, 2013
PubMed

Insights

Increased nitric oxide (NO) inhibits prostate cancer growth by inactivating the androgen receptor (AR) through S-nitrosylation. This novel mechanism targets AR’s DNA-binding domain, offering new therapeutic strategies for advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Antiandrogen therapy targets the androgen receptor (AR) for prostate cancer treatment.
  • This therapy often fails, leading to castration-resistant prostate cancer.
  • Understanding AR regulation is crucial for improving treatment efficacy.

Purpose of the Study:

  • To investigate the role of intracellular nitric oxide (NO) in prostate cancer growth.
  • To elucidate the mechanism by which NO affects AR function.
  • To explore NO-based therapeutic strategies for advanced prostate cancer.

Main Methods:

  • Studied the effect of increased intracellular NO levels on androgen-dependent and castration-resistant prostate tumors.
  • Investigated AR S-nitrosylation at the C601 residue in the DNA-binding domain.
  • Examined the impact of AR S-nitrosylation on DNA-binding activity and subcellular localization.
  • Assessed the role of HSP90 in AR transnitrosylation.
  • Evaluated the efficacy of small-molecule NO donors in inhibiting tumor growth.

Main Results:

  • Increased intracellular NO levels inhibit both androgen-dependent and castration-resistant prostate tumor growth.
  • NO inactivates AR via S-nitrosylation of C601 in the DNA-binding domain.
  • AR S-nitrosylation attenuates DNA-binding activity without altering subcellular distribution.
  • HSP90 facilitates AR transnitrosylation.
  • Small-molecule NO donors effectively inhibit castration-resistant prostate tumor growth.

Conclusions:

  • Intracellular NO represents a novel mechanism for regulating AR function.
  • Targeting AR S-nitrosylation offers a new therapeutic avenue for prostate cancer.
  • Sequential targeting of distinct AR domains may enhance therapeutic outcomes in advanced prostate cancer.

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