The impact of androgen-induced translation in modulating androgen receptor activity
Abstract 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 P...
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2024-11-01
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| Series: | Biology Direct |
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| Online Access: | https://doi.org/10.1186/s13062-024-00550-6 |
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| author | Justus S. Israel Laura-Maria Marcelin Sherif Mehralivand Jana Scholze Jörg Hofmann Matthias B. Stope Martin Puhr Christian Thomas Holger H. H. Erb |
| author_facet | Justus S. Israel Laura-Maria Marcelin Sherif Mehralivand Jana Scholze Jörg Hofmann Matthias B. Stope Martin Puhr Christian Thomas Holger H. H. Erb |
| author_sort | Justus S. Israel |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-7393c3fec1f5417aa2839dba9436cbb5 |
| institution | Kabale University |
| issn | 1745-6150 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
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| series | Biology Direct |
| spelling | doaj-art-7393c3fec1f5417aa2839dba9436cbb52024-11-17T12:14:29ZengBMCBiology Direct1745-61502024-11-0119111710.1186/s13062-024-00550-6The impact of androgen-induced translation in modulating androgen receptor activityJustus S. Israel0Laura-Maria Marcelin1Sherif Mehralivand2Jana Scholze3Jörg Hofmann4Matthias B. Stope5Martin Puhr6Christian Thomas7Holger H. H. Erb8Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität DresdenDepartment of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität DresdenDepartment of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität DresdenDepartment of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität DresdenDepartment of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität DresdenGerman Society of Urology, UroFors Consortium (Natural Scientists in Urological Research)Department of Urology, Medical University of InnsbruckDepartment of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität DresdenDepartment of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität DresdenAbstract 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.https://doi.org/10.1186/s13062-024-00550-6ARPCaNR3C4Androgen deprivation therapy |
| spellingShingle | Justus S. Israel Laura-Maria Marcelin Sherif Mehralivand Jana Scholze Jörg Hofmann Matthias B. Stope Martin Puhr Christian Thomas Holger H. H. Erb The impact of androgen-induced translation in modulating androgen receptor activity Biology Direct AR PCa NR3C4 Androgen deprivation therapy |
| title | The impact of androgen-induced translation in modulating androgen receptor activity |
| title_full | The impact of androgen-induced translation in modulating androgen receptor activity |
| title_fullStr | The impact of androgen-induced translation in modulating androgen receptor activity |
| title_full_unstemmed | The impact of androgen-induced translation in modulating androgen receptor activity |
| title_short | The impact of androgen-induced translation in modulating androgen receptor activity |
| title_sort | impact of androgen induced translation in modulating androgen receptor activity |
| topic | AR PCa NR3C4 Androgen deprivation therapy |
| url | https://doi.org/10.1186/s13062-024-00550-6 |
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