scholarly journals Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes on

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 509
Author(s):  
Eva Estébanez-Perpiñá ◽  
Charlotte L. Bevan ◽  
Iain J. McEwan
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Metastatic Disease ◽  
Structural Information ◽  
The West ◽  
Seminal Paper ◽  
Common Cancer ◽  
Androgen Receptor Activity ◽  
Direct Target

Prostate cancer (PCa) is the most common cancer in men in the West, other than skin cancer, accounting for over a quarter of cancer diagnoses in US men. In a seminal paper from 1941, Huggins and Hodges demonstrated that prostate tumours and metastatic disease were sensitive to the presence or absence of androgenic hormones. The first hormonal therapy for PCa was thus castration. In the subsequent eighty years, targeting the androgen signalling axis, where possible using drugs rather than surgery, has been a mainstay in the treatment of advanced and metastatic disease. Androgens signal via the androgen receptor, a ligand-activated transcription factor, which is the direct target of many such drugs. In this review we discuss the role of the androgen receptor in PCa and how the combination of structural information and functional screenings is continuing to be used for the discovery of new drug to switch off the receptor or modify its function in cancer cells.

scholarly journals Degradation and beyond: Control of androgen receptor activity by the proteasome system

2006 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomasz Jaworski
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Critical Role ◽  
Ubiquitin Proteasome System ◽  
Cancer Therapies ◽  
The Family ◽  
Prostate Cancer Development ◽  
Androgen Receptor Activity ◽  
Ubiquitin Proteasome

AbstractThe androgen receptor (AR) is a transcription factor belonging to the family of nuclear receptors which mediates the action of androgens in the development of urogenital structures. AR expression is regulated post-translationally by the ubiquitin/proteasome system. This regulation involves more complex mechanisms than typical degradation. The ubiquitin/proteasome system may regulate AR via mechanisms that do not engage in receptor turnover. Given the critical role of AR in sexual development, this complex regulation is especially important. Deregulation of AR signalling may be a causal factor in prostate cancer development. AR is the main target in prostate cancer therapies. Due to the critical role of the ubiquitin/proteasome system in AR regulation, current research suggests that targeting AR degradation is a promising approach.

scholarly journals The Von Hippel-Lindau Protein Suppresses Androgen Receptor Activity

2014 ◽  
Vol 28 (2) ◽  
pp. 239-248 ◽  
Author(s):  
Jing Wang ◽  
Wei Zhang ◽  
Wei Ji ◽  
Xing Liu ◽  
Gang Ouyang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Physiological Role ◽  
Transcription Activity ◽  
Von Hippel Lindau ◽  
Prostate Cancer Development ◽  
Androgen Receptor Activity ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Abstract The androgen receptor (AR) plays a pivotal role in prostate homeostasis and prostate cancer development. To understand the mechanism underlying the regulation of the AR holds a promise for developing novel therapeutic approaches for prostate cancer. Here, we show that the Von Hippel-Lindau gene product, pVHL, physically interacts with AR and inhibits AR transcription activity but does not induce AR turnover. Moreover, pVHL also suppresses androgen-induced cell proliferation, implicating a physiological role of pVHL in androgen-induced signaling pathway. In addition, we provide evidence to show that pVHL actually enhanced AR de-ubiquitination instead of inducing AR ubiquitination, uncovering a noncanonical role of pVHL in the ubiquitin proteasome pathway. Our data reveal a novel function of pVHL in the regulation of AR transcription activity, which may expand the scope of pVHL in tumor suppression and provide mechanistic insight into prostate cancer initiation and progression.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

scholarly journals SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana Trnski ◽  
Maja Sabol ◽  
Sanja Tomić ◽  
Ivan Štefanac ◽  
Milanka Mrčela ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Therapy Resistance ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Androgen Independence ◽  
Androgen Receptor Activity ◽  
Signaling Activation ◽  
Androgen Independent

AbstractProstate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

scholarly journals Diagnostic Role of 18F-PSMA-1007 PET/CT in Prostate Cancer Staging: A Systematic Review

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 552
Author(s):  
Salam Awenat ◽  
Arnoldo Piccardo ◽  
Patricia Carvoeiras ◽  
Giovanni Signore ◽  
Luca Giovanella ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Diagnostic Accuracy ◽  
Metastatic Disease ◽  
Cancer Staging ◽  
Relevant Information ◽  
Cochrane Library ◽  
Number Of Patients ◽  
Pet Ct

Background: The use of prostate-specific membrane antigen (PSMA)-targeted agents for staging prostate cancer (PCa) patients using positron emission tomography/computed tomography (PET/CT) is increasing worldwide. We performed a systematic review on the role of 18F-PSMA-1007 PET/CT in PCa staging to provide evidence-based data in this setting. Methods: A comprehensive computer literature search of PubMed/MEDLINE and Cochrane Library databases for studies using 18F-PSMA-1007 PET/CT in PCa staging was performed until 31 December 2020. Eligible articles were selected and relevant information was extracted from the original articles by two authors independently. Results: Eight articles (369 patients) evaluating the role of 18F-PSMA-1007 PET/CT in PCa staging were selected. These studies were quite heterogeneous, but, overall, they demonstrated a good diagnostic accuracy of 18F-PSMA-1007 PET/CT in detecting PCa lesions at staging. Overall, higher primary PCa aggressiveness was associated with higher 18F-PSMA-1007 uptake. When compared with other radiological and scintigraphic imaging methods, 18F-PSMA-1007 PET/CT had superior sensitivity in detecting metastatic disease and the highest inter-reader agreement. 18F-PSMA-1007 PET/CT showed similar results in terms of diagnostic accuracy for PCa staging compared with PET/CT with other PSMA-targeted tracers. Dual imaging with multi-parametric magnetic resonance imaging and 18F-PSMA-1007 PET/CT may improve staging of primary PCa. Notably, 18F-PSMA-1007-PET/CT may detect metastatic disease in a significant number of patients with negative standard imaging. Conclusions: 18F-PSMA-1007 PET/CT demonstrated a good accuracy in PCa staging, with similar results compared with other PSMA-targeted radiopharmaceuticals. This method could substitute bone scintigraphy and conventional abdominal imaging for PCa staging. Prospective multicentric studies are needed to confirm these findings.

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