title: Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer.
abstract: Considerable levels of testosterone and dihydrotestosterone (DHT) are found in prostate cancer (PCa) tissue after androgen deprivation therapy. Treatment of surviving cancer-initiating cells and the ability to metabolize steroids from precursors may be the keystones for the appearance of recurrent tumors. To study this hypothesis, we assessed the expression of several steroidogenic enzymes and stem cell markers in clinical PCa samples and cell cultures during androgen depletion. Gene expression profiles were determined by microarray or qRT-PCR. In addition, we measured cell viability and analyzed stem cell marker expression in DuCaP cells by immunocytochemistry. Seventy patient samples from different stages of PCa, and the PCa cell line DuCaP were included in this study. The androgen receptor (AR) and enzymes (AKR1C3, HSD17B2, HSD17B3, UGT2B15 and UGT2B17 ) that are involved in the metabolism of adrenal steroids were upregulated in castration resistant prostate cancer (CRPC). In vitro, some DuCaP cells survived androgen depletion, and eventually gave rise to a culture adapted to these conditions. During and after this transition, most of the steroidogenic enzymes were upregulated. These cells also are enriched with stem/progenitor cell markers cytokeratin 5 (CK5) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, putative stem/progenitor cell markers CK5, c-Kit, nestin, CD44, c-met, ALDH1A1, α2-integrin, CD133, ABCG2, CXCR4 and POU5F1 were upregulated in clinical CRPC. The upregulation of steroidogenic enzymes and stem cell markers in recurrent tumors suggests that cancer initiating cells can expand by adaptation to their T/DHT deprived environment. Therapies targeting the metabolism of adrenal steroids by the tumor may prove effective in preventing tumor regrowth.
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Minja J
authors.initials: MJ
authors.lastname: Pfeiffer
authors.forename: Frank P
authors.initials: FP
authors.lastname: Smit
authors.forename: John P M
authors.initials: JP
authors.lastname: Sedelaar
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000726:Androgen Antagonists / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D004960:Estradiol Dehydrogenases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D053555:Keratin-5 / Q000378:metabolism; D008297:Male; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013256:Steroids / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D004798:Enzymes; D053555:Keratin-5; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D013256:Steroids; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human