title: De novo steroid biosynthesis in human prostate cell lines and biopsies.
abstract: BACKGROUND
  Intratumoral androgen formation may be a factor in the development of prostate cancer (PCa), particularly castration-resistant prostate cancer (CRPC). To evaluate the ability of the human prostate to synthesize de novo steroids, we examined the expression of key enzymes and proteins involved in steroid biosynthesis and metabolism.
  
  
  METHODS
  Using TissueScan™ Cancer qPCR Arrays and quantitative RT-PCR, we performed comparative gene expression analyses between various prostate cell lines and biopsies, including normal, hyperplastic, cancerous, and androgen-deprived prostate cells lines, as well as normal, benign prostate hyperplasia (BPH), PCa, and CRPC human specimens. These studies were complemented with steroid biosynthesis studies in normal and BPH cells.
  
  
  RESULTS
  Normal human prostate WPMY-1 and WPE1-NA22, benign prostate hyperplasia BPH-1, and cancer PC-3, LNCaP, and VCaP cell lines, as well as normal, BPH, PCa, and CRPC specimens, were used. Although all cell lines express mRNA encoding for hydroxymethylglutaryl-CoA reductase (HMGCR), the mitochondrial translocator protein TSPO and cholesterol side chain cleavage enzyme CYP11A1 were only observed in WPMY-1, BPH-1, and LNCaP cells. HSD3B1, HSD3B2, and CYP17A1 are involved in androgen formation and were not found in most cell lines. WPE1-NA22 and BPH-1 cells were unable to synthesize de novo steroids from mevalonate. Moreover, androgen-deprived cells did not have alterations in the expression of enzymes that could lead to de novo steroid formation. All prostate specimens expressed TSPO and CYP11A1. HSD3B1/2, CYP17A1, HSD17B5, and CYP19A1 mRNA expression was distinct to the profile observed in cells lines. The majority of BPH (90.9%) and PCa (83.1%) specimens contained CYP17A1, compared to control (normal) specimens (46.7%). BPH (82%), PCa (59%), normal (40%), and CRPC (34%) specimens expressed the four key enzymes that metabolize cholesterol to androgens.
  
  
  CONCLUSIONS
  These studies question the use of prostate cell lines to study steroid biosynthesis and demonstrate that human prostate samples contain transcripts encoding for key steroidogenic enzymes and proteins indicating that they have the potential to synthesize de novo steroids. We propose CYP17A1 as a candidate enzyme that can be used for patient stratification and treatment in BPH and PCa.
authors: Research Institute of the McGill University Health Center, Montréal, Québec, Canada.|Department of Medicine, McGill University, Montréal, Québec, Canada.
authors: Monica
authors: M
authors: Sakai
authors: Research Institute of the McGill University Health Center, Montréal, Québec, Canada.|Department of Medicine, McGill University, Montréal, Québec, Canada.
authors: Daniel B
authors: DB
authors: Martinez-Arguelles
authors: Research Institute of the McGill University Health Center, Montréal, Québec, Canada.|Department of Surgery, McGill University, Montréal, Québec, Canada.
authors: Armen G
authors: AG
authors: Aprikian
authors: H. Lee Moffitt Cancer Center and Research Institute, Florida, USA.
authors: Anthony M
authors: AM
authors: Magliocco
authors: Research Institute of the McGill University Health Center, Montréal, Québec, Canada.|Department of Medicine, McGill University, Montréal, Québec, Canada.|H. Lee Moffitt Cancer Center and Research Institute, Florida, USA.|Department of Biochemistry, McGill University, Montréal, Québec, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors: Vassilios
authors: V
authors: Papadopoulos
mesh_terms: D000368:Aged; D000728:Androgens / Q000096:biosynthesis*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D018079:Receptors, GABA / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism
chemical_list: D000728:Androgens; D018079:Receptors, GABA; C499229:TSPO protein, human; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D008798:Mevalonic Acid
keywords: benign prostate hyperplasia; castration-resistant prostate cancer; prostate cancer