Open AccessAndrogen deprivation causes truncation of the C ‐terminal region of androgen receptor in human prostate cancer LNCaP cells
Author(s) -
Harada Naoki,
Inoue Kaoru,
Yamaji Ryoichi,
Nakano Yoshihisa,
Inui Hiroshi
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2012.02250.x
Subject(s) - lncap , androgen receptor , mg132 , chemistry , prostate cancer , androgen insensitivity syndrome , p chloroamphetamine , androgen , transcription factor , cancer research , biology , proteasome inhibitor , receptor , proteasome , biochemistry , cancer , hormone , gene , genetics , serotonergic , serotonin
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 ‐ NH 1 (the N ‐terminal fragment of AR cleaved in the neighborhood of h elix 1 of the ligand‐binding domain), is produced in LNCaP prostatic carcinoma cells. The AR ‐ NH 1 of ~90 kDa was observed in an androgen‐independent LNCaP subline and was further accumulated by the proteasome inhibitor MG 132. MG 132 treatment caused the accumulation of AR ‐ NH 1 even in parent LNCaP cells. AR ‐ NH 1 was produced in the absence of ligand or in the presence of the AR antagonist bicalutamide, whereas AR agonists suppressed its production. AR ‐ NH 1 was detected with different AR antibodies recognizing amino acid residues 1–20 and 300–316 and was also generated from exogenous AR . Both si RNA ‐mediated AR knockdown and treatment with a serine protease inhibitor (4‐(2‐aminoethyl)‐benzenesulfonyl fluoride) reduced AR ‐ NH 1 levels. According to the predicted cleavage site (between amino acid residues 660–685) and its nuclear localization, it is assumed that AR ‐ NH 1 functions as a constitutively active transcription factor. These data suggest that AR ‐ NH 1 is produced under hormone therapy and contributes to the development of castration‐resistant prostate cancer due to its ligand‐independent transcriptional activity. ( Cancer Sci 2012; 103: 1022–1027)