Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential.
Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD(+)-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen-dependent versus castration-resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration-resistant tumor cells expressed higher levels of UGDH, UGT2B15, and UGT2B17. However, the magnitude of androgen-activated UGDH and prostate-specific antigen (PSA) expression, as well as the androgen receptor (AR)-dependent repression of UGT2B15 and UGT2B17, was blunted several-fold in these cells. Consistent with these results, the ligand-activated binding of AR to the PSA promoter and subsequent transcriptional activation were also significantly reduced in castration-resistant cells. Analysis of the UDP-sugar pools and flux through pathways downstream of UDP-glucuronate production revealed that these glucuronidation precursor metabolites were channeled through proteoglycan and glycosaminoglycan biosynthetic pathways, leading to increased surface expression of Notch1. Knockdown of UGDH diminished Notch1 and increased glucuronide output. Overall, these results support a model in which the aberrant partitioning of UDP-glucuronate and other UDP-sugars into alternative pathways during androgen deprivation contributes to the loss of prostate tumor cell androgen sensitivity by promoting altered cell surface proteoglycan expression.
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Brenna M
BM
Zimmer
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Michelle E
ME
Howell
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Qin
Q
Wei
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Linlin
L
Ma
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Trevor
T
Romsdahl
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Eileen G
EG
Loughman
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Jennifer E
JE
Markham
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Javier
J
Seravalli
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA.
Joseph J
JJ
Barycki
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE, 68588-0664, USA. msimpson2@unl.edu.
Melanie A
MA
Simpson
D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000378:metabolism*
C410798:AR protein, human; D000728:Androgens; D020719:Glucuronides; D015778:Minor Histocompatibility Antigens; D011944:Receptors, Androgen; D014533:Uridine Diphosphate Glucose Dehydrogenase; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
Castration resistance; Detoxification; Dihydrotestosterone; LNCaP; Prostate cancer