Characterisations of human prostate stem cells reveal deficiency in class I UGT enzymes as a novel mechanism for castration-resistant prostate cancer
| Autor: | Laura Wilson, Anastasia C. Hepburn, Alejandra Mantilla, Richard Mitter, Craig N. Robson, Hing Y. Leung, SC Williamson, Rakesh Heer |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
cancer stem cells Cancer Research medicine.medical_specialty Cell Survival medicine.drug_class Down-Regulation Biology Real-Time Polymerase Chain Reaction medicine.disease_cause Cell Line Prostate cancer stem cells Prostate Cell Line Tumor androgen receptor Internal medicine medicine Humans RNA Messenger Glucuronosyltransferase Gene Expression Profiling Prostatic Neoplasms Cancer Prostate-Specific Antigen prostate cancer medicine.disease Androgen Up-Regulation Gene Expression Regulation Neoplastic Androgen receptor Adult Stem Cells Prostate-specific antigen Endocrinology medicine.anatomical_structure Oncology Receptors Androgen testosterone Androgens Neoplastic Stem Cells Cancer research Kallikreins Stem cell Transcriptome Translational Therapeutics Carcinogenesis UGT |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/bjc.2013.399 |
| Popis: | Mechanistic studies of tumorigenesis point towards stem cells (SCs) being the cell of origin in prostate cancer initiation, suggesting stem pathways have a crucial role in the early stages of cancer development (Gu et al, 2007; Goldstein et al, 2010; Lawson et al, 2010). Furthermore, known stem pathways have been seen to be aberrantly expressed as the prostate cancer progresses (Linn et al, 2010; Jia et al, 2011; Kregel et al, 2013). Characterisation of the genes at play within prostate SCs, and characterising these same markers in the malignant setting may identify unique therapeutic opportunities for the treatment of prostate cancer. We have recently demonstrated the presence of the androgen receptor (AR) within normal human prostate SCs (Williamson et al, 2012), so identification of specific novel AR pathway processes within these cells will be of particular importance. Such mechanisms may explain the maintenance of androgen ‘addiction' in the malignant setting during cancer progression despite androgen deprivation, as it is established that the AR pathway has diverse roles depending on the degree of prostate differentiation (Gregory et al, 1998; Buchanan et al, 2001; Mousses et al, 2001; Chen et al, 2004; Taplin and Balk, 2004; Attard et al, 2009; Bonkhoff and Berges, 2010; Lee et al, 2012). Human prostate SCs can be enriched by their expressions of α2β1-integrins and CD133 (Richardson et al, 2004). In this work, we describe gene expression signatures associated with SCs (α2β1HI CD133+VE), transiently amplifying (TAP) cells (α2β1HI CD133−VE) and terminally differentiated (TD) cells (α2β1LOW CD133−VE) following the intuitive pathway analysis of transcriptome characterisation of human prostates. Within normal prostate SCs, we discovered a deficiency in class 1 UDP (uridine 5′-diphospho)-glucuronosyltransferase; UGT) enzymes (UGTA1), which are regulators of androgen catabolism. Our functional in vitro models of prostate cancer demonstrated that UGT1A knock down leads to upregulation of prostate-specific antigen (PSA) along with increased cell survival. Furthermore, reduced UGT1A expression was shown to be a feature of clinical prostate cancer that was associated with a poorer prognosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|