Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis

Mol Oncol. 2014 Dec;8(8):1575-87. doi: 10.1016/j.molonc.2014.06.009. Epub 2014 Jun 24.

Abstract

Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function.

Keywords: Androgen receptor; Anti-androgen withdrawal syndrome; BUD31; Crystallography; FxxLF.

Publication types

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

MeSH terms

  • Cell Proliferation / drug effects
  • Chromatin Immunoprecipitation
  • Crystallography, X-Ray
  • Humans
  • Immunoprecipitation
  • Male
  • Peptides / chemistry*
  • Peptides / metabolism*
  • Peptides / pharmacology
  • Prostatic Neoplasms / metabolism*
  • Protein Binding
  • Receptors, Androgen / metabolism*
  • Surface Plasmon Resonance

Substances

  • AR protein, human
  • Peptides
  • Receptors, Androgen