New advances of the androgen receptor in prostate cancer: report from the 1st International Androgen Receptor Symposium

Mehralivand, Sherif; Thomas, Christian; Puhr, Martin; Claessens, Frank; van de Merbel, Arjanneke F.; Dubrovska, Anna; Jenster, Guido; Bernemann, Christof; Sommer, Ulrich; Erb, Holger H. H.

doi:10.1186/s12967-024-04878-5

Cited by 4 publications

References 82 publications

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High throughput screening of nuclear receptors identifies NR4A1, a novel tumor suppressor with potential as a therapeutic target in gallbladder cancer

Sarkar,

Minocha,

Das

et al. 2024

Preprint

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Introduction: Gallbladder cancer(GBC) is one of the most common cancer of the hepato-biliary tract, with a strikingly variable incidence and prevalence across different regions of the world. The Indo-Gangetic belt in Northern India is reported to have one of the highest incidence of about 21/100,000. GBC usually goes unnoticed due to the lack of any early symptoms with two third of GBC cases present late at inoperable stages and have very limited treatment options. Nuclear receptors, a family of 48 members are ligand dependent transcription factors. They are of particular interest in cancer research because of their established role in cancer pathogenesis and their excellent druggability that makes them a suitable therapeutic target. Methodology: mRNA expression 48 nuclear receptors were assessed in GBC tissue samples (n=13) and chronic cholecystitis tissue samples by Nanostring nCounter. The screening identified orphan receptor NR4A1 to be significantly downregulated in GBC. Western blot were performed to further validate the same. We next interrogated the above findings in 2 different gallbladder cancer cell lines, the highly invasive NOZ and the non-invasive TGBC24TKB. In order to investigate the role of NR4A1 in GBC pathogenesis, NOZ cells were treated with cytosporone B (10 micromolar for 24hours) an agonist of NR4A1. On the other hand NR4A1 was knocked down in TGBC24TKB by siRNA. Expression of different markers of proliferation, invasion and epithelial mesenchymal transition was assessed by qPCR. Cell cycle analysis was done using flow cytometry. Results: NR4A1 was one of the top differentially expressed (down regulated) nuclear receptors in GBC both in RNA and protein level. Similar finding was observed in highly invasive cell line NOZ in comparison to TGBC24TKB. Cytosporone B treatment led to upregulation of NR4A1, which resulted in reduction of cell migration as evident by delayed wound healing, reduction in invasion with an increase in G0/G1 populations implying a growth arrest. NR4A1 knockdown in TGBC24TKB lead to reduction in G0/G1 fraction and also increase in proliferation markers like mki67. Conclusion: NR4A1 in our study acts as a tumor suppressor, loss of which seems to provide a growth and survival advantage to GBC cells. NR4A1 activation by agonist reduced cell proliferation and invasion. We therefore propose NR4A1 as a novel biomarker in GBC with its loss associated with overall poor outcome. Hence its agonists may emerge as a potential candidate for neo-adjuvant therapy for advanced gallbladder cancer.

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High throughput screening of nuclear receptors identifies NR4A1, a novel tumor suppressor with potential as a therapeutic target in gallbladder cancer

Sarkar,

Minocha,

Das

et al. 2024

Preprint

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Emerging frontiers in androgen receptor research for prostate Cancer: insights from the 2nd international androgen receptor Symposium

Israel,

Marcelin,

Thomas

et al. 2024

J Exp Clin Cancer Res

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Continued exploration of the androgen receptor (AR) is crucial, as it plays pivotal roles in diverse diseases such as prostate cancer (PCa), serving as a significant therapeutic focus. Therefore, the Department of Urology Dresden hosted an international meeting for scientists and clinical oncologists to discuss the newest advances in AR research. The 2nd International Androgen Receptor Symposium was held in Dresden, Saxony, Germany, from 26–27.04.2024, organised by Dr. Holger H.H. Erb. Following the format of the first meeting, more than 35 scientists from 8 countries attended the event to discuss recent developments, research challenges, and identification of venues in AR research. An important new feature was the involvement of PhD students and young investigators, acknowledging the high scientific quality of their work. The symposium included three covers: new advances from clinical research, basic and translational research, and novel strategies to target AR. Moreover, based on its increasing clinical relevance, a PSMA theranostic mini-symposium was added at the end of the AR symposium to allow the audience to discuss the newest advances in PSMA theranostic. This report focuses on the highlights and discussions of the meeting.

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The impact of androgen-induced translation in modulating androgen receptor activity

Israel,

Marcelin,

Mehralivand

et al. 2024

Biol Direct

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Introduction Dysregulated androgen receptor (AR) activity is central to various diseases, particularly prostate cancer (PCa), in which it drives tumour initiation and progression. Consequently, antagonising AR activity via anti-androgens is an indispensable treatment option for metastatic PCa. However, despite initial tumour remission, drug resistance occurs. Therefore, the AR signalling pathway has been intensively investigated. However, the role of AR protein stability in AR signalling and therapy resistance has not yet been deciphered. Therefore, this study aimed to investigate the role of AR protein changes in transactivity and assess its mechanism as a possible target in PCa. Methods LNCaP, C4-2, and 22Rv1 cells were treated with R1881, enzalutamide, cycloheximide, and Rocaglamide. Mass spectrometry analyses were performed on LNCaP cells to identify the pathways enriched by the treatments. Western blotting was performed to investigate AR protein levels and localisation changes. Changes in AR transactivity were determined by qPCR. Results Mass spectrometry analyses were performed on LNCaP cells to decipher the molecular mechanisms underlying androgen- and antiandrogen-induced alterations in the AR protein. Pathway analysis revealed the enrichment of proteins involved in different pathways that regulate translation. Translational and proteasome inhibitor experiments revealed that these AR protein changes were attributable to modifications in translational activity. Interestingly, the effects on AR protein levels in castration-resistant PCa (CRPC) cells C4-2 or enzalutamide-resistant cells 22Rv1 were less prominent and non-existent. This outcome was similarly observed in the alteration of AR transactivation, which was suppressed in hormone-sensitive prostate cancer (HSPC) LNCaP cells by translational inhibition, akin to the effect of enzalutamide. In contrast, treatment-resistant cell lines showed only a slight change in AR transcription. Conclusion This study suggests that in HSPC, AR activation triggers a signalling cascade that increases AR protein levels by enhancing its translation rate, thereby amplifying AR activity. However, this mechanism appears to be dysregulated in castration-resistant PCa cells.

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New advances of the androgen receptor in prostate cancer: report from the 1st International Androgen Receptor Symposium

Cited by 4 publications

References 82 publications

High throughput screening of nuclear receptors identifies NR4A1, a novel tumor suppressor with potential as a therapeutic target in gallbladder cancer

High throughput screening of nuclear receptors identifies NR4A1, a novel tumor suppressor with potential as a therapeutic target in gallbladder cancer

Emerging frontiers in androgen receptor research for prostate Cancer: insights from the 2nd international androgen receptor Symposium

The impact of androgen-induced translation in modulating androgen receptor activity

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