title: Calcitriol-induced prostate-derived factor: autocrine control of prostate cancer cell growth.
abstract: Calcitriol (1alpha,25-dihydroxycholecalciferol) seems to play an important role in the complex control of prostate cell growth. It inhibits proliferation and induces differentiation and apoptosis in prostate cancer cells. However, the molecular mechanisms of the antiproliferative activity of calcitriol are not completely understood. The expression of prostate-derived factor (PDF), a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to be associated with proapoptotic and antimitotic activities. We show that calcitriol induces PDF expression in LNCaP human prostate cancer cells in a concentration- and time-dependent manner. In LNCaP cells, the suppression of cell growth by calcitriol is accompanied by stimulation of PDF mRNA and protein synthesis. Human recombinant PDF inhibits LNCaP cell growth. We do not detect any effect of PDF-specific antibody on the basal growth of LNCaP cells, but this antibody partially reverses the suppression of LNCaP cell growth by calcitriol, suggesting that the effect of calcitriol on cell growth is at least partially mediated by PDF. In PC-3 cells, which are less responsive to the growth-inhibitory effect of calcitriol, it has no effect on PDF expression. We do not detect an effect of recombinant PDF on SMAD phosphorylation in LNCaP cells, but ERK1/2 kinases are transiently phosphorylated in response to PDF, which suggests that in LNCaP cells PDF may exert its action through pathway alternative to the classical TGF-beta signaling pathway. The present study describes the regulation of PDF, the proapoptotic protein of the TGF-beta superfamily, by calcitriol in androgen-responsive prostate cancer cells. This is a new link between calcitriol and growth factors of TGF-beta superfamily in the control of prostate cell growth.
authors.affiliation: Department of Anatomy, Medical School, University of Tampere, Tampere, Finland. nadya.nazarova@uta.fi
authors.forename: Nadja
authors.initials: N
authors.lastname: Nazarova
authors.forename: Shengjun
authors.initials: S
authors.lastname: Qiao
authors.forename: Olga
authors.initials: O
authors.lastname: Golovko
authors.forename: Yan-Ru
authors.initials: YR
authors.lastname: Lou
authors.forename: Pentti
authors.initials: P
authors.lastname: Tuohimaa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D052160:Benzothiazoles; D019485:Bone Morphogenetic Proteins / Q000187:drug effects* / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018076:DNA, Complementary / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055436:Growth Differentiation Factor 15; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000187:drug effects; D012334:RNA, Neoplasm / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D019485:Bone Morphogenetic Proteins; D002120:Calcium Channel Agonists; D018076:DNA, Complementary; D004273:DNA, Neoplasm; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D008565:Membrane Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; D013844:Thiazoles; D013196:Dihydrotestosterone; D003609:Dactinomycin; D014050:Toluene; D014638:Vanadates; C121565:pifithrin; D002117:Calcitriol