Androgen receptor reverts dexamethasone‑induced inhibition of prostate cancer cell proliferation and migration

Guo, Ju; Ma, Ke; Xia, Haimei; Chen, Qingke; Li, Lei; Deng, Jun; Sheng, Jiajing; Hong, Yan‐Yan; Hu, Jielun

doi:10.3892/mmr.2018.8566

Cited by 11 publications

(12 citation statements)

References 36 publications

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“…This compound did not affect on PTEN levels as well as the ER and PR receptors in T47D cells. Similarly, although both DU-145 and PC-3 cells express the glucocorticoid receptor (Guo et al, 2018), ASR-600 still failed to inhibit the growth of both cell lines. Recently, Sharp et al (2019) reported that while AR-V7 is rarely expressed in primary CaP, it is predominantly expressed in CRPC and frequently detected in CaP cases following ADT treatment and further increased following treatment with abiraterone or enzalutamide.…”

Section: Discussionmentioning

confidence: 97%

Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7

Chandrasekaran

Tyagi²,

Saran³

et al. 2023

Front. Pharmacol.

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We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR− CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.

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Section: Discussionmentioning

confidence: 97%

Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7

Chandrasekaran

Tyagi²,

Saran³

et al. 2023

Front. Pharmacol.

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“…GRs compete with AR for DNA-binding (the GR is also negatively regulated by active AR signaling). [ 20 , 35 ] Although the 2 receptors share nearly identical DNA-binding specificities, the target genes overlap by <50% and execute unique functions in vivo. [ 20 , 35 ] Different abilities of AR and GR to interact with relatively inaccessible chromatin result in divergent binding and corresponding gene regulation.…”

Section: Discussionmentioning

confidence: 99%

“…[ 20 , 35 ] Although the 2 receptors share nearly identical DNA-binding specificities, the target genes overlap by <50% and execute unique functions in vivo. [ 20 , 35 ] Different abilities of AR and GR to interact with relatively inaccessible chromatin result in divergent binding and corresponding gene regulation. [ 36 ] There might also be subtle differences in the DNA-binding preferences between AR and GR.…”

Section: Discussionmentioning

confidence: 99%

Is the glucocorticoid receptor a key player in prostate cancer?: A literature review

Sakellakis

Flores

2022

Medicine

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Glucocorticoids act through the glucocorticoid receptor (GR) and exert pleiotropic effects in different cancer types. In prostate cancer cells, GR and androgen receptor (AR) share overlapping transcriptomes and cistromes. Under enzalutamide treatment, GR signaling can bypass AR activation and promote castration resistance via the expression of a subset of AR-target genes. However, GR-dependent growth under enhanced antiandrogen inhibition occurs only in a subset of primed cells. On the other hand, glucocorticoids have been used successfully in the treatment of prostate cancer for many years. In the context of AR signaling, GR competes with AR for DNA-binding and has the potential to halt the proliferation rate of prostate cancer cells. Their target genes overlap by <50% and they execute unique functions in vivo. In addition, even when AR and GR upregulate the same transcriptional target gene, the effect might not be identical in magnitude. Besides being able to drive tumor proliferation, GR is also a key player in prostate cancer cell survival. Stimulation of GR activity can undermine the effects of enhanced antiandrogen treatment, chemotherapy and radiotherapy. GR activation in prostate cancer can increase prosurvival gene expression. Identifying the full spectrum of GR activity will inform the optimal use of glucocorticosteroids in prostate cancer. It will also determine the best strategies to target the protumorigenic effects of GR.

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“…Moreover, different therapeutic modalities such as dexamethasone, nitric oxide, and chloroquine, which are effective in managing COVID-19, are reported to have anti-androgenic effects and suppression of TMPRSS2 ( Cronauer et al., 2007 ; Guo et al., 2018 ; Chi et al., 2020 ). Taken together, based on the current findings, testosterone is implicated in the facilitation of SARS-CoV-2 infection through upregulation of TMPRSS2 and androgen receptor (AR) activation.…”

Section: Harmful Role Of Testosterone In Covid-19mentioning

confidence: 99%

Testosterone in COVID-19: An Adversary Bane or Comrade Boon

Al-Kuraishy

Al-Gareeb

Faidah

et al. 2021

Front. Cell. Infect. Microbiol.

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COVID-19 is a pandemic disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), which leads to pulmonary manifestations like acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In addition, COVID-19 may cause extra-pulmonary manifestation such as testicular injury. Both high and low levels of testosterone could affect the severity of COVID-19. Herein, there is substantial controversy regarding the potential role of testosterone in SARS-CoV-2 infection and COVID-19 severity. Therefore, the present study aimed to review and elucidate the assorted view of preponderance regarding the beneficial and harmful effects of testosterone in COVID-19. A related literature search in PubMed, Scopus, Web of Science, Google Scholar, and Science Direct was done. All published articles related to the role of testosterone and COVID-19 were included in this mini-review. The beneficial effects of testosterone in COVID-19 are through inhibition of pro-inflammatory cytokines, augmentation of anti-inflammatory cytokines, modulation of the immune response, attenuation of oxidative stress, and endothelial dysfunction. However, its harmful effects in COVID-19 are due to augmentation of transmembrane protease serine 2 (TMPRSS2), which is essential for cleaving and activating SARS-CoV-2 spike protein during acute SARS-CoV-2 infection. Most published studies illustrated that low testosterone levels are linked to COVID-19 severity. A low testosterone level in COVID-19 is mainly due to testicular injury, the primary source of testosterone.

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Androgen receptor reverts dexamethasone‑induced inhibition of prostate cancer cell proliferation and migration

Cited by 11 publications

References 36 publications

Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7

Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7

Is the glucocorticoid receptor a key player in prostate cancer?: A literature review

Testosterone in COVID-19: An Adversary Bane or Comrade Boon

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