Dehydroepiandrosterone Activates Mutant Androgen Receptors Expressed in the Androgen-Dependent Human Prostate Cancer Xenograft CWR22 and LNCaP Cells

Tan, Jiann An; Sharief, Yousuf; Hamil, Katherine G.; Gregory, Christopher; Zang, De Ying; Sar, Madhabananda; Gumerlock, Paul H.; White, Ralph W. deVere; Pretlow, Thomas G.; Harris, S. E.; Wilson, Elizabeth M.; Mohler, James L.; French, Frank S.

doi:10.1210/mend.11.4.9906

Cited by 273 publications

(68 citation statements)

References 45 publications

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“…1, lanes 1-3). Full-length AR was also evident in extracts of the CWR22 human prostate cancer xenograft propagated in nude mice (Wainstein et al 1994, Nagabhushan et al 1996, Tan et al 1997) from both androgen-dependent tumors and recurrent tumors that arose after prolonged androgen deprivation by castration (Fig. 1, lanes 5-6).…”

Section: Ar In Cell Lines and Tissuesmentioning

confidence: 92%

The putative androgen receptor-A form results from in vitro proteolysis

Gregory

He²,

Wilson³

2001

Journal of Molecular Endocrinology

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Activation domains in the 114 kDa androgen receptor (AR) NH 2 -and carboxyl-terminal regions are thought to contribute to different extents to AR-mediated transactivation. We investigated using anti-peptide antibodies whether smaller AR forms that migrate like the previously described 87 kDa AR-A occur in vivo resulting in constitutive or increased gene activation. Immunoblots of prostate cancer and fibroblast cell culture extracts revealed 114 and 84 kDa AR forms. Antibody mapping indicated the 84 kDa AR lacked the ligand-binding domain and comigrated with the constitutively active AR fragment AR1-660. AR expressed in COS cells was 114 and 92 kDa. Migration of the 92 kDa AR was slightly slower than that of a 90 kDa expressed fragment that was designed to initiate at the second methionine (residue 189) and lacked the NH 2 -terminal FxxLF interaction sequence. The 92 kDa AR did not result from alternative initiation since it was observed when the second methionine was changed to alanine. Optimization of extraction conditions indicated that both 84 and 92 kDa forms resulted from in vitro proteolytic cleavage and that cleavage by caspase-3 could account for the 92 kDa form. The results suggest that AR forms with gel mobility similar to that of the previously described 87 kDa AR-A result from in vitro proteolytic cleavage of NH 2 -or carboxyl-terminal regions during cell extraction and storage and that smaller forms with increased transcriptional activity do not occur in vivo.

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Section: Ar In Cell Lines and Tissuesmentioning

confidence: 92%

The putative androgen receptor-A form results from in vitro proteolysis

Gregory

He²,

Wilson³

2001

Journal of Molecular Endocrinology

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“…The mutation is located in exon H of the AR gene and leads to an exchange of the wild-type threonine (position 877) to alanine. It has been demonstrated in several studies that hormones that bind to the mutated LNCaP AR with increased affinity stimulate cellular proliferation and enhance transcriptional activation function of that AR (Veldscholte et al 1990a,b, 1992, Montgomery et al 1992, Tan et al 1997. These hormones are estrogenic and progestagenic steroids, adrenal androgens, and the non-steroidal antiandrogens hydroxyflutamide and nilutamide.…”

Section: Ar Structural Alterations In Prostate Cancermentioning

confidence: 99%

“…Transcription activation function of the MDA PCa 2a AR is strongly induced by the glucocorticoid hormones, cortisol and cortisone (Zhao et al 2000), which promote the growth of that cell line. In the prostate cancer xenograft CWR 22, there is an exchange of histidine at position 874 with tyrosine (Tan et al 1997). Histidine 874 does not contact ligand and the mutation found in the prostate cancer xenograft most probably affects binding of AR coactivators and their regulation of AR function (McDonald et al 2000).…”

Section: Ar Structural Alterations In Prostate Cancermentioning

confidence: 99%

“…Among substances which stimulate the activity of mutated AR in prostate cancer, testosterone precursors (adrenal androgens) and metabolites, as well as antiandrogens, are particularly important. AR activation by naturally occurring androgenic precursors and metabolites is described for the LNCaP AR, AR 715 ValǞMet, 730 ValǞMet, and 874 HisǞTyr (Culig et al 1993b, Peterziel et al 1995, Tan et al 1997. Hydroxyflutamide and bicalutamide were considered more promising antiandrogenic drugs than cyproterone acetate because of their non-steroidal structure.…”

Section: Ar Structural Alterations In Prostate Cancermentioning

confidence: 99%

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Androgen receptors in prostate cancer.

Čulig¹,

Klocker²,

Bartsch³

et al. 2002

Endocrine-Related Cancer

244

201

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The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1β, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens. Endocrine-Related Cancer (2002) 9 155-170

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“…The other major phenotypic output of common LBD mutations is antagonist-agonist switching (Supplementary Table 1), which likely explains the withdrawal syndrome observed after cessation of firstgeneration antagonists seen in 15-30% of patients (Small et al 2004). T878A confers agonist properties to flutamide and nilutamide, H875Y to nilutamide and W742C/L to bicalutamide (Veldscholte et al 1990, Suzuki et al 1996, Tan et al 1997, Hara et al 2003, Azad et al 2015, O'Neill et al 2015, Lallous et al 2016. Interestingly, O'Neill and coworkers recently demonstrated that T878A inhibited bicalutamide-activated W742L (O'Neill et al 2015) in what may represent the first evidence of antagonism arising from the heterodimerization of distinct AR mutants.…”

Section: Gata2 Oct1mentioning

confidence: 99%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

148

122

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The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

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Dehydroepiandrosterone Activates Mutant Androgen Receptors Expressed in the Androgen-Dependent Human Prostate Cancer Xenograft CWR22 and LNCaP Cells

Cited by 273 publications

References 45 publications

The putative androgen receptor-A form results from in vitro proteolysis

The putative androgen receptor-A form results from in vitro proteolysis

Androgen receptors in prostate cancer.

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

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