Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium

Stanbrough, Michael; Leav, Irwin; Kwan, Paul; Bubley, Glenn J.; Balk, Steven P.

doi:10.1073/pnas.191235898

Cited by 154 publications

(118 citation statements)

References 70 publications

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“…On the basis of the pleiotropic activities of IFNs, some downstream mediators, however, may also trigger tumorigenesis, especially when the upregulation is uncoupled from complex IFN-induced responses. In PCa, IFNs not only inhibit the proliferation of PCa cells (Sica et al, 1994) but also upregulate the AR expression (Sica et al, 1994;Basrawala et al, 2006) known to exhibit growth-promoting effects (Stanbrough et al, 2001;Berger et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The androgen receptor (AR) plays a critical role in the growth, differentiation and function of the prostate, and is also involved in the initiation and progression of PCa. Animal models clearly indicate that AR overexpression in prostatic epithelial cells triggers proliferation and oncogenic transformation (Stanbrough et al, 2001;Berger et al, 2004). In PCa patients, high AR levels are associated with aggressive clinicopathological features and a decreased biochemical recurrence-free survival .…”

Section: Introductionmentioning

confidence: 99%

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Expression, regulation and function of the ISGylation system in prostate cancer

et al. 2009

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The androgen receptor (AR) plays a crucial role in the modulation of prostate cell proliferation and is involved in the development and progression of prostate cancer (PCa). An understanding of the complex regulation of AR provides novel treatment options for PCa. Here, we show (i) that the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), and most enzymes involved in ISG15 conjugation were upregulated in tumor samples versus in non-malignant tissues of PCa patients and (ii) that the expression of these components significantly differed between tumors in patients treated with and without androgen ablation. Using PCa cell lines as in vitro models, the specific androgen-mediated, ARdependent regulation of the ISGylation components was confirmed. In addition, the ISGylation system controls AR mRNA and protein expressions, as overexpression of Ube1L as a limiting ISGylation factor in the AR þ androgensensitive PCa cell line, LNCaP, results in significant AR upregulation, accompanied by an increased proliferation even under androgen deprivation. Accordingly, Ube1L knockdown decreased the AR expression. Thus, this study describes for the first time the modulation of AR expression by ISGylation components, which affects the proliferation of PCa cells, thereby providing evidence for a novel function of the ISGylation system in malignant transformation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression, regulation and function of the ISGylation system in prostate cancer

et al. 2009

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“…It is well known that the AR is essential for cellular survival in prostate cancer cells, [8][9][10][11][12][13][14][15] but its downstream effectors are not fully listed. In this study, we sought to identify novel downstream mediators responsible for AR-dependent survival.…”

Section: Discussionmentioning

confidence: 99%

“…7 The etiology of hormone-refractory progression may have various molecular causes, but a critical role of the AR has emerged. [8][9][10][11] We and others have recently showed that eliminating AR expression led to a profound apoptotic response in AR-positive prostate cancer cells, suggesting that the AR is essential for cellular survival in prostate cancers. [12][13][14][15] However, the downstream effectors that facilitate AR-dependent survival are not fully elucidated.…”

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confidence: 99%

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

et al. 2007

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Androgen receptor (AR) is a critical factor in the development and progression of prostate cancer. We and others recently demonstrated that eliminating AR expression leads to apoptotic cell death in AR-positive prostate cancer cells. To understand the mechanisms of AR-dependent survival, we performed a genome-wide search for AR-regulated survival genes. We found that serum/glucocorticoid-induced protein kinase-1 (SGK-1) mRNA levels were significantly upregulated after androgen stimulation, which was confirmed to be AR dependent. Promoter analysis revealed that the AR interacted with the proximal and distal regions of the sgk1 promoter, leading to sgk-1 promoter activation after androgen stimulation. Functional assays demonstrated that SGK-1 was indispensable for the protective effect of androgens on cell death induced by serum starvation. SGK-1 overexpression not only rescued cells from AR small-interfering RNA (siRNA)-induced apoptosis, but also enhanced AR transactivation, even in the absence of androgen. Additionally, SGK-1 siRNA reduced AR transactivation, indicating a positive feedback effect of SGK-1 expression on AR-mediated gene expression and cellular survival. Taken together, our data suggest that SGK-1 is an androgen-regulated gene that plays a pivotal role in AR-dependent survival and gene expression.

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“…Both androgen and androgen receptor (AR) are recognized risk factors in the development of prostate cancer [17][18][19][20]. These observations are further corroborated by genetic evidence from transgenic mouse models, suggesting that increased AR signaling in the prostate is linked to an increase in precancerous lesions [21]. Since elevated level of androgen causes enhancement of prostate cancer, reduction of circulating levels of androgens is central to the treatment of prostate cancer [22,23].…”

Section: Introductionmentioning

confidence: 99%

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

Hong

Seeram

Heber

2008

The Journal of Nutritional Biochemistry

135

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Prostate cancer is dependent on circulating testosterone in its early stages and is treatable with radiation and surgery. However, recurrent prostate tumors advance to an androgen-independent state where they progress in the absence of circulating testosterone leading to metastasis and death. During the development of androgen independence, prostate cancer cells are known to increase intracellular testosterone synthesis which maintains cancer cell growth in the absence of significant amounts of circulating testosterone. Overexpression of the androgen receptor (AR) occurs in androgenindependent prostate cancer and has been proposed as another mechanism promoting the development of androgen independence. The LNCaP-AR cell line is engineered to overexpress AR but is otherwise similar to the widely studied LNCaP cell line. We have previously shown that pomegranate extracts inhibit both androgen-dependent and androgen-independent prostate cancer cell growth. In the present study, we examined the effects of pomegranate polyphenols, ellagitanninrich extract and whole juice extract on the expression of genes for key androgen synthesizing enzymes and the AR. We measured expression of the HSD3B2, AKR1C3 and SRD5A1 genes for the respective androgen synthesizing enzymes in LNCaP, LNCaP-AR, and DU-145 human prostate cancer cells. A two-fold suppression of gene expression was considered statistically significant. Pomegranate polyphenols inhibited gene expression and AR most consistently in the LNCaP-AR cell line (P =.05). Therefore, inhibition by pomegranate polyphenols of gene expression involved in androgen synthesis enzymes and the AR may be of particular importance in androgen-independent prostate cancer cells and the subset of human prostate cancers where AR is upregulated.

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Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium

Cited by 154 publications

References 70 publications

Expression, regulation and function of the ISGylation system in prostate cancer

Expression, regulation and function of the ISGylation system in prostate cancer

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

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