Overcoming Persistent Dependency on Androgen Signaling after Progression to Castration-Resistant Prostate Cancer

Yamaoka, Masuo; Hara, Takahito; Kusaka, Masami

doi:10.1158/1078-0432.ccr-10-0255

Cited by 72 publications

(83 citation statements)

References 60 publications

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“…However, several likely interconnected mechanisms of castration resistance have been proposed. For example, alterations in intraprostatic androgen production or metabolism ("intracrine" androgen production) in castration-resistant prostate cancer (4,5) could lead to elevated local androgen concentrations in the setting of low serum androgen levels. Alternatively, the abundance or activity of androgen receptors (ARs) and their various transcriptional coregulators might be modified in castration-resistant prostate cancer cells so that they respond to lower concentrations of androgen or other steroids (6).…”

Section: Introductionmentioning

confidence: 99%

Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

Sen¹,

Castro²,

DeFranco³

et al. 2012

J. Clin. Invest.

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In prostate cancer, the signals that drive cell proliferation change as tumors progress from castration-sensitive (androgen-dominant) to castration-resistant states. While the mechanisms underlying this change remain uncertain, characterization of common signaling components that regulate both stages of prostate cancer proliferation is important for developing effective treatment strategies. Here, we demonstrate that paxillin, a known cytoplasmic adaptor protein, regulates both androgen-and EGF-induced nuclear signaling. We show that androgen and EGF promoted MAPK-dependent phosphorylation of paxillin, resulting in nuclear translocation of paxillin. We found nuclear paxillin could then associate with androgen-stimulated androgen receptor (AR). This complex bound AR-sensitive promoters, retaining AR within the nucleus and regulating ARmediated transcription. Nuclear paxillin also complexed with ERK and ELK1, mediating c-FOS and cyclin D1 expression; this was followed by proliferation. Thus, paxillin is a liaison between extranuclear MAPK signaling and nuclear transcription in response to androgens and growth factors, making it a potential regulator of both castration-sensitive and castration-resistant prostate cancer. Accordingly, paxillin was required for normal growth of human prostate cancer cell xenografts, and its expression was elevated in human prostate cancer tissue microarrays. Paxillin is therefore a potential biomarker for prostate cancer proliferation and a possible therapeutic target for prostate cancer treatment. IntroductionProstate cancer is associated with significant morbidity and mortality and is the second most common cancer among men worldwide. One feature of prostate cancer progression is its apparent change in androgen responsiveness over time. At diagnosis, locally advanced prostate cancers are treated successfully by prostatectomy, irradiation, and/or anti-androgen therapy, suggesting that tumor cells are dependent on androgens for continued growth and survival. In contrast, despite treatment, many advanced tumors enter a more aggressive castration-resistant state after 18-24 months. This observation suggests fundamental changes in the extracellular triggers and intracellular signaling pathways that regulate proliferation and cell migration (1-3) in aggressive tumors. The reasons for this dramatic transformation in phenotype are not well understood. However, several likely interconnected mechanisms of castration resistance have been proposed. For example, alterations in intraprostatic androgen production or metabolism ("intracrine" androgen production) in castration-resistant prostate cancer (4, 5) could lead to elevated local androgen concentrations in the setting of low serum androgen levels. Alternatively, the abundance or activity of androgen receptors (ARs) and their various transcriptional coregulators might be modified in castration-resistant prostate cancer cells so that they respond to lower concentrations of androgen or other steroids (6). Finally, prostate cancer cells might ad...

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Section: Introductionmentioning

confidence: 99%

Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

Sen¹,

Castro²,

DeFranco³

et al. 2012

J. Clin. Invest.

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“…The mechanisms proposed to contribute to ablation-resistant growth of prostate cancer all involve reactivation of the AR under ablation conditions (reviewed in reference 46). A major mechanistic advance has been the realization that the ablation-resistant phenotype in many tumors is accompanied by the fusion of TMPRSS2 (along with its AR enhancer) and ETS transcription factor genes, allowing AR stimulation of the powerful secondary transcription factor family (46) or by the expression of AR constitutively active splicing variants (40). Furthermore, the involvement of the AR in the ablation-resistant phenotype was clearly demonstrated by the disruption of AR expression, which inhibited the proliferation of ablation-resistant prostate cancer cells in the absence of androgens (48).…”

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confidence: 99%

Dynamic Nucleosome-Depleted Regions at Androgen Receptor Enhancers in the Absence of Ligand in Prostate Cancer Cells

Andreu-Vieyra

Lai

Berman

et al. 2011

Molecular and Cellular Biology

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Nucleosome positioning at transcription start sites is known to regulate gene expression by altering DNA accessibility to transcription factors; however, its role at enhancers is poorly understood. We investigated nucleosome positioning at the androgen receptor (AR) enhancers of TMPRSS2, KLK2, and KLK3/PSA in prostate cancer cells. Surprisingly, a population of enhancer modules in androgen-deprived cultures showed nucleosome-depleted regions (NDRs) in all three loci. Under androgen-deprived conditions, NDRs at the TMPRSS2 enhancer were maintained by the pioneer AR transcriptional collaborator GATA-2. Androgen treatment resulted in AR occupancy, an increased number of enhancer modules with NDRs without changes in footprint width, increased levels of histone H3 acetylation (AcH3), and dimethylation (H3K4me2) at nucleosomes flanking the NDRs. Our data suggest that, in the absence of ligand, AR enhancers exist in an equilibrium in which a percentage of modules are occupied by nucleosomes while others display NDRs. We propose that androgen treatment leads to the disruption of the equilibrium toward a nucleosome-depleted state, rather than to enhancer de novo "remodeling." This allows the recruitment of histone modifiers, chromatin remodelers, and ultimately gene activation. The "receptive" state described here could help explain AR signaling activation under very low ligand concentrations.Nucleosomes are the basic units of eukaryotic chromatin, each one containing ϳ146 bp of DNA wrapped around an octamer of histone core proteins, which in turn are separated by linker DNA sequences of variable length (39). Nucleosomes play a pivotal role in chromatin structure, and their differential occupancy at promoters (transcription start sites) regulates gene expression by altering DNA accessibility (39). For instance, a nucleosome-depleted region (NDR) at transcriptional start sites correlates with gene expression, whereas the positioning of a nucleosome over the transcriptional start site results in gene repression (23). In contrast, the role of nucleosome positioning at other regulatory regions, particularly distal ones such as enhancers, is less well characterized. Interestingly, nucleosome turnover was recently shown to be increased at genes and regulatory elements (9), suggesting that this process may control nucleosome density and the existence of NDRs.Enhancers are nondirectional regulatory elements that control promoter activity at a distance on linear DNA. Several histone marks, including mono-and dimethylated H3K4 (H3K4me1 and H3K4me2) and acetylated H3K9,14 (AcH3), have been shown to correlate or be associated with regions that display enhancer activity, although H3K4me2 and AcH3, along with the trimethylation version of H3K4 (H3K4me3), are also located at transcriptional start sites (16,44). Enhancers generally contain DNA recognition motifs for transcription factors which, upon binding, regulate gene expression by looping to the transcriptional start sites of their target genes.The androgen receptor (AR) is a ligan...

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“…Pregnenolone and progesterone are converted to 17a-hydroxypregnenolone and 17a-hydroxyprogesterone, respectively, by the 17-hydroxylase activity of CYP17A1, and then to dehydroepiandrosterone (DHEA) and androstenedione by C17,20-lyase activity. DHEA and androstenedione are precursors of testosterone [40]. To obtain the best result in AA treatment, it is necessary to administrate AA together with low-dose of corticosteroids in order to inhibit ACTH stimulation and, as a consequence, to increase mineralocorticoids.…”

Section: Treatment Of Advanced Diseasementioning

confidence: 99%

Gene interference strategies as a new tool for the treatment of prostate cancer

et al. 2015

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Prostate cancer (PCa) is one of the most common cancer in men. It affects older men and the incidence increases with age; the median age at diagnosis is 67 years. The diagnosis of PCa is essentially based on three tools: digital rectal exam, serum concentration of prostate specific antigen, and transrectal ultrasound-guided biopsy. Currently, the therapeutic treatments of this cancer are different and range from the prostatectomy to hormonal therapy, to radiation therapy, to immunotherapy, and to chemotherapy. However, additional efforts are required in order to find new weapons for the treatment of metastatic setting of disease. The purpose of this review is to highlight new therapeutic strategies based on gene interference; in fact, numerous siRNA and miRNA in the therapeutic treatment of PCa are reported below.

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Overcoming Persistent Dependency on Androgen Signaling after Progression to Castration-Resistant Prostate Cancer

Cited by 72 publications

References 60 publications

Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

Dynamic Nucleosome-Depleted Regions at Androgen Receptor Enhancers in the Absence of Ligand in Prostate Cancer Cells

Gene interference strategies as a new tool for the treatment of prostate cancer

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