A Role of Androgen Receptor Protein in Cell Growth of an Androgen-Independent Prostate Cancer Cell Line

Furutani, Takashi; Takeyama, Ken-ichi; Koutoku, Hiroshi; S, Itó; Taniguchi, Nobuaki; Suzuki, Eriko; Kudoh, Masafumi; Shibasaki, Masayuki; Shikama, Hisataka; Kato, Shigeaki

doi:10.1271/bbb.69.2236

Cited by 10 publications

(8 citation statements)

References 22 publications

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“…Although depletion of androgen in AR-positive prostate cancer cells in vitro leads to cell cycle arrest instead of cell death, recent studies utilizing siRNA strategies have demonstrated that targeted ablation of AR leads to cell death in vitro. [46][47][48][49] Collectively, these observations strongly support the contention that AR controls cell survival in response to androgen ablation.…”

Section: Influence Of Ar On Prostate Cancer Cell Survivalsupporting

confidence: 60%

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

Comstock¹,

Knudsen²

2007

Cell Cycle

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Section: Influence Of Ar On Prostate Cancer Cell Survivalsupporting

confidence: 60%

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

Comstock¹,

Knudsen²

2007

Cell Cycle

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“…In our previous study we observed that siRNA knockdown of AR using two independent siRNA constructs inhibited PSA expression in C4-2B cells grown in the absence and presence of androgens (19). Recently it was also shown that cell proliferation was attenuated by siRNA-mediated knockdown of the AR (13). In the present experiments we knocked down AR and analyzed histone modifications at the PSA locus.…”

Section: Resultsmentioning

confidence: 65%

Locus-Wide Chromatin Remodeling and Enhanced Androgen Receptor-Mediated Transcription in Recurrent Prostate Tumor Cells

Li¹,

Shen²,

Wantroba³

et al. 2006

Molecular and Cellular Biology

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Prostate cancers (PCas) become resistant to hormone withdrawal through increased androgen receptor (AR) signaling. Here we show increased AR-mediated transcription efficiency in PCa cells that have acquired the ability to grow in low concentrations of androgen. Compared to androgen-dependent PCa cells, these cells showed increased activity of transiently transfected reporters and increased mRNA synthesis relative to levels of AR occupancy of the prostate-specific antigen (PSA) gene. The locus also displayed up to 10-fold-higher levels of histone H3-K9/K14 acetylation and H3-K4 methylation across the entire body of the gene. Although similar increased mRNA expression and locus-wide histone acetylation were also observed at another kallikrein locus (KLK2), at a third AR target locus (TMPRSS2) increased gene expression and locus-wide histone acetylation were not seen in the absence of ligand. Androgen-independent PCa cells have thus evolved three distinctive alterations in AR-mediated transcription. First, increased RNA polymerase initiation and processivity contributed to increased gene expression. Second, AR signaling was more sensitive to ligand. Third, locus-wide chromatin remodeling conducive to the increased gene expression in the absence of ligand was apparent and depended on sustained AR activity. Therefore, increased AR ligand sensitivity as well as locus-specific chromatin alterations contribute to basal gene expression of a subpopulation of specific AR target genes in androgen-independent PCa cells. These features contribute to the androgen-independent phenotype of these cells.The molecular processes that mediate transcription orchestrate cell proliferation, differentiation, and disease progression. Central to this regulation is the dynamic organization and modification of nucleosomes, the basic repeating unit of chromatin that is comprised of 146 bp of DNA wrapped around histone octamers. Accessibility to transcription factors and activation of genes largely depend on diverse posttranslational modifications of amino termini (36, 47) and the more recently implicated globular domains of histones (6). These modifications include acetylation, phosphorylation, and methylation, which covalently add acetyl, phospho, and methyl groups, respectively, to specific residues of core histones. The well-characterized acetylation and methylation of lysines in histones H3 and H4 are highly correlated with transcriptional activation. Acetylation, catalyzed by histone acetyltransferases such as p300/CBP, is reversed by the activity of histone deacetylases, which mediate transcriptional repression (21). Methylation at histone H3 (K4) is catalyzed by specific methyltransferases often found in large complexes such as ALL-1 (32). This process is reversed by the action of a recently identified lysinespecific histone demethylase, LSD1 (39, 40). The complex interactions between the different histone tail modifications have led to the "histone code hypothesis," which suggests that specific histone modifications affect and interac...

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“…Of note, DU145 and PC3 cell lines, which no longer express AR, are representative of a proportion of advanced prostate tumors where AR is no longer required for tumor growth [11]. Several studies evaluated the role of AR in CRCaP cells in vitro , leading to contradictory conclusions: Gosh et al, showed that the main driver of CRCaP cells' division was p70S6 kinase, and not AR [14] and two studies showed that RNAi-induced AR silencing in these cells produced only a limited [15] or a non statistically significant effect [16]. In contrast, Zegarra-Moro et al [13] showed that the microinjection of AR antibodies almost completely arrested C4-2 cells' proliferation, whereas Liao et al [17] reported that AR silencing induced their massive apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, although AR is functional in most recurrent tumors [5], [12], disrupting AR signaling once the resistant phenotype is established, may not be sufficient to halt the tumor growth. Studies set up, in cultured cells, to test this hypothesis lead to contradictory conclusions [13], [14], [15], [16], [17]. Using RNA interference to study in vivo the role of AR in CRCaP, we demonstrate here that tumors that escaped hormonal manipulations are still dependent on the androgen receptor for their in vivo growth: AR silencing in tumors inhibits cells' proliferation, induces apoptosis and inhibits angiogenesis.…”

Section: Introductionmentioning

confidence: 97%

SIRNA-Directed In Vivo Silencing of Androgen Receptor Inhibits the Growth of Castration-Resistant Prostate Carcinomas

et al. 2007

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BackgroundProstate carcinomas are initially dependent on androgens, and castration or androgen antagonists inhibit their growth. After some time though, tumors become resistant and recur with a poor prognosis. The majority of resistant tumors still expresses a functional androgen receptor (AR), frequently amplified or mutated.Methodology/Principal FindingsTo test the hypothesis that AR is not only expressed, but is still a key therapeutic target in advanced carcinomas, we injected siRNA targeting AR into mice bearing exponentially growing castration-resistant tumors. Quantification of siRNA into tumors and mouse tissues demonstrated their efficient uptake. This uptake silenced AR in the prostate, testes and tumors. AR silencing in tumors strongly inhibited their growth, and importantly, also markedly repressed the VEGF production and angiogenesis.Conclusions/SignificanceOur results demonstrate that carcinomas resistant to hormonal manipulations still depend on the expression of the androgen receptor for their development in vivo. The siRNA-directed silencing of AR, which allows targeting overexpressed as well as mutated isoforms, triggers a strong antitumoral and antiangiogenic effect. siRNA-directed silencing of this key gene in advanced and resistant prostate tumors opens promising new therapeutic perspectives and tools.

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A Role of Androgen Receptor Protein in Cell Growth of an Androgen-Independent Prostate Cancer Cell Line

Cited by 10 publications

References 22 publications

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

Locus-Wide Chromatin Remodeling and Enhanced Androgen Receptor-Mediated Transcription in Recurrent Prostate Tumor Cells

SIRNA-Directed In Vivo Silencing of Androgen Receptor Inhibits the Growth of Castration-Resistant Prostate Carcinomas

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