title: 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.affiliation: Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan. harada@biochem.osakafu-u.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yamaji
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inui
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009570:Nitriles; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; D014105:Tosyl Compounds; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; C053541:bicalutamide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde