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Characterisations of human prostate stem cells reveal deficiency in class I UGT enzymes as a novel mechanism for castration-resistant prostate cancer.
- Source :
-
British journal of cancer [Br J Cancer] 2013 Aug 20; Vol. 109 (4), pp. 950-6. Date of Electronic Publication: 2013 Jul 23. - Publication Year :
- 2013
-
Abstract
- Background: Evidence increasingly supports that prostate cancer is initiated by the malignant transformation of stem cells (SCs). Furthermore, many SC-signalling pathways are shown to be shared in prostate cancer. Therefore, we planned transcriptome characterisation of adult prostate SCs as a strategy to consider new targets for cancer treatment.<br />Methods: Intuitive pathway analysis was used for putative target discovery in 12 matched selections of human prostate SCs, transiently amplifying cells and terminally differentiated cells. These were pooled into three groups according to the stage of differentiation for mRNA microarray analysis. Targets identified were validated using uncultured primary tissue (n=12), functional models of prostate cancer and a tissue microarray consisting of benign (n=42) and malignant prostate (n=223).<br />Results: A deficiency in class 1 UDP glucuronosyltransferase (UGT) enzymes (UGT1A) was identified in prostate SCs, which are involved in androgen catabolism. Class 1 UGT enzyme expression was also downregulated in cancer SCs and during progression to metastatic castration-resistant prostate cancer (CRPC). Reduction of UGT1A expression in vitro was seen to improve cell survival and increase androgen receptor (AR) activity, as shown by upregulation of prostate-specific antigen expression.<br />Interpretation: Inactivation of intracellular androgen catabolism represents a novel mechanism to maintain AR activity during CRPC.
- Subjects :
- Androgens metabolism
Cell Line
Cell Line, Tumor
Cell Survival
Down-Regulation
Gene Expression Profiling
Glucuronosyltransferase metabolism
Humans
Kallikreins metabolism
Male
Prostate cytology
Prostate-Specific Antigen metabolism
Prostatic Neoplasms genetics
Real-Time Polymerase Chain Reaction
Receptors, Androgen metabolism
Transcriptome
Up-Regulation
Adult Stem Cells enzymology
Gene Expression Regulation, Neoplastic
Glucuronosyltransferase genetics
Neoplastic Stem Cells enzymology
Prostate enzymology
Prostatic Neoplasms enzymology
RNA, Messenger analysis
Subjects
Details
- Language :
- English
- ISSN :
- 1532-1827
- Volume :
- 109
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- British journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 23880823
- Full Text :
- https://doi.org/10.1038/bjc.2013.399