title: Sorbitol dehydrogenase expression is regulated by androgens in the human prostate.
abstract: Sorbitol is an intermediate in the polyol pathway, which converts from glucose to fructose by sorbitol dehydrogenase (SORD). Androgens are essential for the development of prostate cancer. We studied castration-induced gene expression changes in the human prostate using the GeneChip array, and identified SORD as being androgen-regulated in the human prostate. A putative androgen-responsive regulatory region at the SORD 5' promoter was identified using promoter deletion constructs in a luciferase reporter assay in COS-7 cells. Chromatin immunoprecipitation assay was used to assess the binding of androgen receptor to suggested androgen responsive regulatory region. Finally, the expression of SORD in the human prostate was evaluated in 29 prostate tissue samples by immunohistochemistry. The expression of SORD decreased after castration. Androgen supplementation to the LNCaP prostate cancer cell line led to a 7.5-fold increase in SORD mRNA expression. Furthermore, a chromatin immunoprecipitation assay proved that the androgen receptor can bind to this putative androgen-responsive regulatory region. Finally, the expression of SORD in the human prostate was localised to epithelial cells of both benign and malignant prostate tissue by immunohistochemistry. In prostate cancer, increased immunostaining was associated with high Gleason patterns and high serum prostate-specific antigen concentrations. These results show that SORD is a novel androgen-regulated gene in the human prostate and suggest the need for more detailed analysis of the physiological role of SORD in the prostate.
authors.affiliation: Department of Pathology, University of Oulu, Oulu, Finland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szabó
authors.forename: Jenni
authors.initials: J
authors.lastname: Hämäläinen
authors.forename: Ildikó
authors.initials: I
authors.lastname: Loikkanen
authors.forename: Anne-Mari
authors.initials: AM
authors.lastname: Moilanen
authors.forename: Pasi
authors.initials: P
authors.lastname: Hirvikoski
authors.forename: Timo
authors.initials: T
authors.lastname: Väisänen
authors.forename: Timo K
authors.initials: TK
authors.lastname: Paavonen
authors.forename: Markku H
authors.initials: MH
authors.lastname: Vaarala
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001706:Biopsy; D019556:COS Cells; D002369:Castration; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D007064:L-Iditol 2-Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D014162:Transfection
chemical_list: C410798:AR protein, human; D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D007064:L-Iditol 2-Dehydrogenase; D017430:Prostate-Specific Antigen