Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation

Mukhopadhyay, Nishit K.; Kim, Jayoung; Cinar, Bekir; Ramachandran, Aruna; Hager, Martin H.; Vizio, Dolores Di; Adam, Rosalyn M.; Rubin, Mark A.; Raychaudhuri, Pradip; Benedetti, Arrigo De; Freeman, Michael R.

doi:10.1158/0008-5472.can-08-2308

Cited by 54 publications

(54 citation statements)

References 47 publications

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“…A ϳ0.5 kb region of the AR 5Ј-UTR containing binding sites for the nucleic acid-binding protein HnRNPK has been implicated in the attenuation of AR translation initiation by PI 3-kinase/Akt/mTOR signaling (53). A mechanism by which TOK-001 (and to a lesser extent abiraterone alcohol) alters AR translation initiation is supported by the reduced expression of a reporter gene fused to the AR 5Ј-UTR.…”

Section: Discussionmentioning

confidence: 99%

Direct Regulation of Androgen Receptor Activity by Potent CYP17 Inhibitors in Prostate Cancer Cells

Soifer

Souleimanian

et al. 2012

Journal of Biological Chemistry

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Background: Abiraterone and TOK-001 are inhibitors of CYP17 activity, a crucial enzyme for the synthesis of testosterone in prostate cancer cells. Results: These 17-heteroarylsteroids also directly down-regulate the expression and activation of the androgen receptor. Conclusion: TOK-001 and abiraterone, down-regulate androgen receptor signaling via multiple mechanisms. Significance: Anti-CYP17 17-heteroarylsteroids may have multiple mechanisms of action in prostate cancer cells.

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Section: Discussionmentioning

confidence: 99%

Direct Regulation of Androgen Receptor Activity by Potent CYP17 Inhibitors in Prostate Cancer Cells

Soifer

Souleimanian

et al. 2012

Journal of Biological Chemistry

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“…41,42 Finally, SVIL and HNRNPK, which contain hsa-miR-604 and hsa-miR-7 respectively, are also important in androgen hormone signalling. 43,44 Understanding the differential expression of miRNA in the adipose tissue of obese patients is useful to advance understanding of mechanisms important to the development of NAFLD and NASH. Hopefully, novel insights into NAFLD pathogenesis could facilitate the development of the novel treatment modalities, such as miRNA replacement therapy.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Estep

Armistead

Hossain

et al. 2010

Aliment Pharmacol Ther

124

115

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Aliment Pharmacol Ther 2010; 32: 487–497SummaryBackground Progression of non‐alcoholic fatty liver disease (NAFLD) can be facilitated by soluble molecules secreted by visceral adipose tissue (VAT). MicroRNAs (miRNAs) are likely to regulate some of these molecular pathways involved in pathogenesis of NAFLD.Aim To profile miRNA expression in the visceral adipose tissue of patients with NAFLD.Methods Visceral adipose tissue samples were collected from NAFLD patients and frozen. Patients with biopsy‐proven NAFLD were divided into non‐alcoholic steatohepatitis (NASH) (n = 12) and non‐NASH (n = 12) cohorts controlled for clinical and demographic characteristics. Extracted total RNA was profiled using TaqMan Human MicroRNA arrays. Univariate Mann–Whitney comparisons and multivariate regression analysis were performed to compare miRNA profiles.Results A total of 113 miRNA differentially expressed between NASH patients and non‐NASH patients (P < 0.05). Of these, seven remained significant after multiple test correction (hsa‐miR‐132, hsa‐miR‐150, hsa‐miR‐433, hsa‐miR‐28‐3p, hsa‐miR‐511, hsa‐miR‐517a, hsa‐miR‐671). Predicted target genes for these miRNAs include insulin receptor pathway components (IGF1, IGFR13), cytokines (CCL3, IL6), ghrelin/obestatin gene, and inflammation‐related genes (NFKB1, RELB, FAS). In addition, two miRNA species, hsa‐miR‐197 and hsa‐miR‐99, were significantly associated with pericellular fibrosis in NASH patients (P < 0.05). Levels of IL‐6 in the serum negatively correlated with the expression levels of all seven miRNAs capable of down regulating IL‐6 encoding gene.Conclusions miRNA expression from VAT may contribute to the pathogenesis of NAFLD – a finding which may distinguish relatively simple steatosis from NASH. This could help identify potential targets for pharmacological treatment regimens and candidate biomarkers for NASH.

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“…8 Using proteomic analysis of the nuclear matrix, we previously reported that hnRNP K, a member of the hnRNP family with pleiotropic functions, [9][10][11][12] was overexpressed in PC specimens with involvement of seminal vesicles and that its expression level was closely correlated with Gleason score and poor prognosis. 13 It has been recently demonstrated that hnRNP K regulates the expression of AR by a posttranscriptional mechanism 14 and that NE cells in malignant prostatic tissues show no androgen receptors. 15 Based on these observations, in the present study we investigated the role of hnRNP K in neuroendocrine and adenocarcinoma samples making use of in vitro models of NED and of the mouse TRAMP model, where expression of the SV40 T-antigen under the probasin promoter causes the appearance of adenocarcinomas expressing androgen receptors and the rapid progression of neuroendocrine carcinomas.…”

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Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Ciarlo

Benelli

Barbieri

et al. 2011

Intl Journal of Cancer

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Current diagnostic tools cannot predict clinical failure and androgen-independent disease progression for patients with prostate cancer (PC). The survival signaling pathways of prostate cells play a central role in the progression of tumors to a neuroendocrine (NE) phenotype. NE cells demonstrate attributes that suggest that they are an integral part of the signaling cascade leading to castration-resistant PC. In this study, making use of in vitro neuroendocrine differentiation (NED) of human LNCaP and mouse TRAMP-C2 cells after androgen withdrawal, and of the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we characterized a sequence of molecular events leading to NED and identified a number of markers that could be detectable by routine analyses not only in castration resistant PC but also in hormone naïve PC at the time of initial diagnosis. We found that NED associates with AKT activation that in turn regulates heterogeneous nuclear ribonucleoprotein K (hnRNP K), androgen receptor (AR) and b-catenin levels. Addition of molecules targeting membrane-bound receptors and protein kinases blocks NE differentiation in LNCaP and TRAMP-C2 cells. The extent of AKT phosphorylation and hnRNP K, AR and b-catenin levels may have a potential value as prognostic indicators discriminating between androgen-responsive and unresponsive cells and could be used as molecular targets to monitor the anti-tumor action of new therapeutic protocols based on antireceptor agents and/or neuroendocrine hormone antagonists.PC is one of the most common malignancies among males in the western world and a major health problem in many industrialized countries. PC develops and progresses under the influence of androgenic steroids. This influence is consistent with the use of androgen depletion therapies to treat patients with advanced disease.1 However, most patients finally relapse with hormone-refractory prostate cancer and available treatment options are only palliative. Therefore, an understanding of what drives progression to androgen independence is critical. The prostate is known to be dependent not only on androgens but also on growth factors and neuropeptides secreted by NE cells that maintain normal prostate function and play a role in the development of pathological conditions.2 Adult prostate gland possesses basal (proliferating) cells, secretory (luminal) cells and the less abundant (<0.1%) NE cells. Approximately 10% of prostatic carcinoma reveals extensive and multifocal NE features and the presence of NE markers is usually associated with poor prognosis. 3,4 Interestingly, along with the androgen-independent status, an increase in the number of NE cells has been reported in some studies and long-term androgen ablation therapy tends to select prostate tumor populations that are enriched in NE cells.5 These cells lack nuclear androgen receptor 6 ; thus they represent an androgen-insensitive cell phenotype in the prostate and it has been hypothesized that NE cells can lead to the development and growth of androgen-refract...

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Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation

Abstract: The regulation of androgen receptor (AR) expression in prostate cancer is still poorly understood.

Cited by 54 publications

References 47 publications

Direct Regulation of Androgen Receptor Activity by Potent CYP17 Inhibitors in Prostate Cancer Cells

Direct Regulation of Androgen Receptor Activity by Potent CYP17 Inhibitors in Prostate Cancer Cells

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

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