Androgen receptors in endocrine‐therapy‐resistant human prostate cancer

Kwast, Theodorus H. van der; Schalken, Jack A.; Winter, J A Ruizeveld de; Vroonhoven, C. C. J. Van; Mulder, E.; Boersma, W.J.A.; Trapman, Jan

doi:10.1002/ijc.2910480206

Cited by 335 publications

(188 citation statements)

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“…The most important finding was the proof that the AR is expressed not only in primary prostate tumors 4,5 but also in their corresponding metastatic lesions, as shown in vivo in immunohistochemical studies. 6,7 It has become clear that progression from androgen-dependent to androgen-independent prostate tumor growth is not associated with loss of the AR.…”

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confidence: 88%

Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides

et al. 2000

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Currently available methods for treatment of human prostatic carcinoma aim to inactivate the androgen receptor (AR) by androgen deprivation or blockade with anti-androgens. Failure of endocrine therapy and tumor progression is characterized by androgenindependent growth despite high levels of AR expression in metastatic disease. We inhibited AR expression in LNCaP prostate tumor cells by using antisense AR oligodeoxynucleotides (ODNs) and explored whether antisense AR treatment would be conceivable as a therapy for advanced prostate cancer. Among the various AR antisense ODNs tested, a 15-base ODN targeting the CAG repeats encoding the poly-glutamine region of the AR (as750/15) was found to be most effective. Treatment of LNCaP cells with as750/15 reduced AR expression to ϳ2% within 24 hours compared with mock-treated controls. AR down-regulation resulted in significant cell growth inhibition, strongly reduced secretion of the androgen-regulated prostate-specific antigen, reduction of epidermal growth factor receptor expression, and an increase in apoptotic cells. Mis-sense and mismatched control ODNs had no or only slight effects. Antisense inhibition was also very efficient in LNCaP-abl cells, a subline established after long-term androgen ablation of LNCaP cells, resulting in inhibition of AR expression and cell proliferation that was similar to that seen for parental LNCaP cells. This study shows that inhibition of AR expression by antisense AR ODNs may be a promising new approach for treatment of advanced human prostate cancer. Cancer Gene Therapy (2000) 7, 997-1007

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confidence: 88%

Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides

et al. 2000

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“…Recent evidence also androgen-independent disease. However, it is now known that the majority of metastatic deposits of prostate cancer continue to express androgen receptor (54)(55)(56), and current theories of androgen independence have focussed on the presence of a functioning androgen receptor (i.e. AR hypersensitivity, promiscuity, amplification etc.)…”

Section: Statistical Analysesmentioning

confidence: 99%

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

et al. 2007

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tom@pelhamcourt.clara.co.uk Introduction Epigenetic silencing mechanisms are increasingly thought to play a major role in the development of human cancers, including prostate cancer. The two major epigenetic regulatory mechanisms involve alterations in DNA methylation and histone acetylation status. Promoter CpG island hypermethylation and histone hypoacetylation, catalysed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) respectively, are associated with transcriptional repression. Evidence in other cancers suggests the two mechanisms are dynamically linked, yet few studies have examined the potential interaction of the two pathways in prostate cancer. Here we report a synergistic, apoptotic effect of treatment with a demethylating agent and a histone deacetylase inhibitor on cultured prostate cancer cells, with associated re-expression of the putative antiproliferative agent oestrogen receptor beta.Methods LNCaP, DU-145 and PC-3 cells were pre-treated with the DNMT inhibitor 5'-aza-2'-deoxycytidine (5-AZAC) for 72 hours followed by 24 hours combined treatment with 5-AZAC and the HDAC inhibitor trichostatin A (TSA). Following treatment, cells were either processed for cell proliferation, cell toxicity, cell viability and apoptosis assays, or harvested for quantitative real-time RT-PCR gene expression analyses. Assessed target genes were oestrogen receptor beta (ERβ), androgen receptor (AR), progesterone receptor (PGR) and prostate specific antigen (PSA). ResultsIn all cell-lines co-treatment with 5-AZAC and TSA was associated with significantly reduced cell proliferation when compared with control groups (p<0.05); associated reduced cell viability and increased cell death was seen in all cases. Caspase activation was significantly increased in the co-treatment group, indicating that apoptosis was a major mechanism of cell death. Most marked effects were seen in the androgen-dependent, AR-positive LNCaP cell-line. In all cell-lines a marked synergistic re-expression of ERβ was identified in the co-treatment group, a finding which was not seen for either AR or PSA. A similar re-expression of PGR was also identified. ConclusionsAt concentrations associated with gene re-expression, the DNA demethylating agent 5-AZAC and the HDAC inhibitor TSA co-operate in an additive and synergistic way to induce apoptosis in prostate cancer cell-lines. Increased apoptosis in the co-treatment group was associated with marked re-expression of ERβ, which is an intriguing finding, raising the possibility of further targeting of prostate cancer cells with ERβ-selective agents such as phytooestrogens and selective oestrogen receptor modulators (SERMs).

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“…Immunohistochemical staining of tumor biopsies showed that the AR is expressed in most prostate cancers, often at higher levels in relapsed tumors than in primary tumors. 5,6 AR gene amplification has been reported in up to 30% of recurrent tumors. [7][8][9] How AR upregulation might confer a growth advantage under androgen ablation conditions is still not fully understood.…”

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Androgen receptor modifications in prostate cancer cells upon long‐termandrogen ablation and antiandrogen treatment

Marques¹,

Erkens-Schulze²,

Ridder³

et al. 2005

Intl Journal of Cancer

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To study the mechanisms whereby androgen-dependent tumors relapse in patients undergoing androgen blockade, we developed a novel progression model for prostate cancer. The PC346C cell line, established from a transurethral resection of a primary tumor, expresses wild-type (wt) androgen receptor (AR) and secretes prostate-specific antigen (PSA). Optimal proliferation of PC346C requires androgens and is inhibited by the antiandrogen hydroxyflutamide. Orthotopic injection in the dorsal-lateral prostate of castrated athymic nude mice did not produce tumors, whereas fast tumor growth occurred in sham-operated males. Three androgen-independent sublines were derived from PC346C upon long-term in vitro androgen deprivation: PC346DCC, PC346Flu1 and PC346Flu2. PC346DCC exhibited androgeninsensitive growth, which was not inhibited by flutamide. AR and PSA were detected at very low levels, coinciding with background AR activity in a reporter assay, which suggests that these cells have bypassed the AR pathway. PC346Flu1 and PC346Flu2 were derived by culture in steroid-stripped medium supplemented with hydroxyflutamide. PC346Flu1 strongly upregulated AR expression and showed 10-fold higher AR activation than the parental PC346C. PC346Flu1 proliferation was inhibited in vitro by R1881 at 0.1 nM concentration, consistent with a slower tumor growth rate in intact males than in castrated mice. PC346Flu2 carries the well-known T877A AR mutation, causing the receptor to become activated by diverse nonandrogenic ligands including hydroxyflutamide. Array-based comparative genomic hybridization revealed little change between the various PC346 lines. The common alterations include gain of chromosomes 1, 7 and 8q and loss of 13q, which are frequently found in prostate cancer. In conclusion, by in vitro hormone manipulations of a unique androgen-dependent cell line expressing wtAR, we successfully reproduced common AR modifications observed in hormone-refractory prostate cancer: downregulation, overexpression and mutation. ' 2005 Wiley-Liss, Inc.

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Androgen receptors in endocrine‐therapy‐resistant human prostate cancer

Cited by 335 publications

References 20 publications

Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides

Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

Androgen receptor modifications in prostate cancer cells upon long‐termandrogen ablation and antiandrogen treatment

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