Androgen deprivation causes truncation of the C-terminal region of androgen receptor in human prostate cancer LNCaP cells.

Abstract

The androgen receptor (AR) acts as a ligand-dependent transcription factor, whereas mutant AR lacking the C-terminal ligand-binding domain functions in a ligand-independent manner. In the present study we report that the C-terminal truncated AR, which we named AR-NH1 (the N-terminal fragment of AR cleaved in the neighborhood of helix 1 of the ligand-binding domain), is produced in LNCaP prostatic carcinoma cells. The AR-NH1 of ~90 kDa was observed in an androgen-independent LNCaP subline and was further accumulated by the proteasome inhibitor MG132. MG132 treatment caused the accumulation of AR-NH1 even in parent LNCaP cells. AR-NH1 was produced in the absence of ligand or in the presence of the AR antagonist bicalutamide, whereas AR agonists suppressed its production. AR-NH1 was detected with different AR antibodies recognizing amino acid residues 1-20 and 300-316 and was also generated from exogenous AR. Both siRNA-mediated AR knockdown and treatment with a serine protease inhibitor (4-(2-aminoethyl)-benzenesulfonyl fluoride) reduced AR-NH1 levels. According to the predicted cleavage site (between amino acid residues 660-685) and its nuclear localization, it is assumed that AR-NH1 functions as a constitutively active transcription factor. These data suggest that AR-NH1 is produced under hormone therapy and contributes to the development of castration-resistant prostate cancer due to its ligand-independent transcriptional activity.

• Authors: Naoki Harada, Kaoru Inoue, Ryoichi Yamaji, Yoshihisa Nakano, Hiroshi Inui
• Journal: Cancer science (Cancer Sci) Vol. 103 Issue 6 Pg. 1022-7 (Jun 2012) ISSN: 1349-7006 [Electronic] England
• PMID: 22360658 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Japanese Cancer Association.

Chemical References

• Androgen Receptor Antagonists
• Androgens
• Anilides
• Antineoplastic Agents
• Cysteine Proteinase Inhibitors
• Leupeptins
• Nitriles
• RNA, Small Interfering
• Receptors, Androgen
• Serine Proteinase Inhibitors
• Sulfones
• Tosyl Compounds
• 4-(2-aminoethyl)benzenesulfonylfluoride
• bicalutamide
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Androgen Receptor Antagonists (pharmacology)
• Androgens (metabolism)
• Anilides (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cysteine Proteinase Inhibitors (pharmacology)
• Humans
• Leupeptins (pharmacology)
• Male
• Nitriles (pharmacology)
• Prostatic Neoplasms (metabolism, pathology)
• RNA Interference
• RNA, Small Interfering
• Receptors, Androgen (chemistry, genetics, metabolism)
• Serine Proteinase Inhibitors (pharmacology)
• Sulfones (pharmacology)
• Tosyl Compounds (pharmacology)