The role of androgen in determining differentiation and regulation of androgen receptor expression in the human prostatic epithelium transient amplifying population.
Abnormal differentiation in epithelial stem cells or their immediate proliferative progeny, the transiently amplifying population (TAP), may explain malignant pathogenesis in the human prostate. These models are of particular importance as differing sensitivities to androgen among epithelial cell subpopulations during differentiation are recognised and may account for progression to androgen independent prostate cancer. Androgens are crucial in driving terminal differentiation and their indirect effects via growth factors from adjacent androgen responsive stroma are becoming better characterised. However, direct effects of androgen on immature cells in the context of a prostate stem cell model have not been investigated in detail and are studied in this work. In alpha2beta1hi stem cell enriched basal cells, androgen analogue R1881 directly promoted differentiation by the induction of differentiation-specific markers CK18, androgen receptor (AR), PSA and PAP. Furthermore, treatment with androgen down-regulated alpha2beta1 integrin expression, which is implicated in the maintenance of the immature basal cell phenotype. The alpha2beta1hi cells were previously demonstrated to lack AR expression and the direct effects of androgen were confirmed by inhibition using the anti-androgen bicalutamide. AR protein expression in alpha2beta1hi cells became detectable when its degradation was repressed by the proteosomal inhibitor MG132. Stratifying the alpha2beta1hi cells into stem (CD133(+)) and transient amplifying population (TAP) (CD133(-)) subpopulations, AR mRNA expression was found to be restricted to the CD133(-) (TAP) cells. The presence of a functional AR in the TAP, an androgen independent subpopulation for survival, may have particular clinical significance in hormone resistant prostate cancer, where both the selection of immature cells and functioning AR regulated pathways are involved.
Heer
R
R
Urology Research Group, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, UK. rakesh.heer@ncl.ac.uk
Robson
C N
CN
Shenton
B K
BK
Leung
H Y
HY
D000071916:AC133 Antigen; D000135:Acid Phosphatase; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D053538:Keratin-18 / Q000096:biosynthesis; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D015741:Metribolone / Q000494:pharmacology*; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D010455:Peptides / Q000032:analysis; D010641:Phenotype; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D045165:Testosterone Congeners / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000494:pharmacology
D000071916:AC133 Antigen; C410798:AR protein, human; D000726:Androgen Antagonists; D000813:Anilides; D015703:Antigens, CD; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D038982:Integrin alpha2beta1; C488421:KRT18 protein, human; D053538:Keratin-18; D007976:Leupeptins; D009570:Nitriles; C000606023:PROM1 protein, human; D010455:Peptides; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D014105:Tosyl Compounds; D051523:Fibroblast Growth Factor 7; D015741:Metribolone; C053541:bicalutamide; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; D017430:Prostate-Specific Antigen; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde