Glucocorticoid receptor upregulation increases radioresistance and triggers androgen independence of prostate cancer

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.

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Gene Expression Profile, Androgen Independence and Prostate Cancer

Journal of Cancer Therapy ◽

10.4236/jct.2012.35082 ◽

2012 ◽

Vol 03 (05) ◽

pp. 637-644

Author(s):

Maxwell Omabe ◽

Joel C. Onyeanusi ◽

Nworie Amos ◽

Martin Ezeani ◽

Simon Imakwu Okekpa

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Gene Expression Profile ◽

Expression Profile ◽

Androgen Independence

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Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

Endocrine Related Cancer ◽

10.1530/erc-15-0343 ◽

2015 ◽

Vol 23 (1) ◽

pp. 35-45 ◽

Cited By ~ 22

Author(s):

Jan Kroon ◽

Martin Puhr ◽

Jeroen T Buijs ◽

Geertje van der Horst ◽

Daniëlle M Hemmer ◽

...

Keyword(s):

Prostate Cancer ◽

Glucocorticoid Receptor ◽

Cell Lines ◽

Chemotherapy Resistance ◽

Clinical Problem ◽

Dependent Manner ◽

Ru 486 ◽

Docetaxel Resistance ◽

Docetaxel Treatment

Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa.

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Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer

eLife ◽

10.7554/elife.20183 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 38

Author(s):

Jianneng Li ◽

Mohammad Alyamani ◽

Ao Zhang ◽

Kai-Hsiung Chang ◽

Michael Berk ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Glucocorticoid Receptor ◽

Tumor Cells ◽

Target Genes ◽

Hydroxysteroid Dehydrogenase ◽

Mouse Xenograft ◽

Ubiquitin E3 Ligase ◽

Metabolic Mechanism ◽

Stimulation Of

Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

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Tumor suppressor REIC/Dkk-3 and its co-chaperone SGTA: Their interaction and role to control castration-resistant prostate cancer by the release from androgen independence and malignancy

European Urology Supplements ◽

10.1016/s1569-9056(19)30052-1 ◽

2019 ◽

Vol 18 (1) ◽

pp. e68-e69

Author(s):

T. Sadahira ◽

Y. Maruyama ◽

Y. Mitsui ◽

K. Wada ◽

K. Edamura ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Suppressor ◽

Castration Resistant Prostate Cancer ◽

Androgen Independence ◽

Castration Resistant

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Enzalutamide response in a panel of prostate cancer cell lines reveals a role for glucocorticoid receptor in enzalutamide resistant disease

Scientific Reports ◽

10.1038/s41598-020-78798-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rebecca Smith ◽

Moqing Liu ◽

Tiera Liby ◽

Nora Bayani ◽

Elmar Bucher ◽

...

Keyword(s):

Prostate Cancer ◽

Glucocorticoid Receptor ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Lines ◽

Response To Therapy ◽

Model Systems ◽

Prostate Cancer Cell Lines

AbstractRepresentative in vitro model systems that accurately model response to therapy and allow the identification of new targets are important for improving our treatment of prostate cancer. Here we describe molecular characterization and drug testing in a panel of 20 prostate cancer cell lines. The cell lines cluster into distinct subsets based on RNA expression, which is largely driven by functional Androgen Receptor (AR) expression. KLK3, the AR-responsive gene that encodes prostate specific antigen, shows the greatest variability in expression across the cell line panel. Other common prostate cancer associated genes such as TMPRSS2 and ERG show similar expression patterns. Copy number analysis demonstrates that many of the most commonly gained (including regions containing TERC and MYC) and lost regions (including regions containing TP53 and PTEN) that were identified in patient samples by the TCGA are mirrored in the prostate cancer cell lines. Assessment of response to the anti-androgen enzalutamide shows a distinct separation of responders and non-responders, predominantly related to status of wild-type AR. Surprisingly, several AR-null lines responded to enzalutamide. These AR-null, enzalutamide-responsive cells were characterized by high levels of expression of glucocorticoid receptor (GR) encoded by NR3C1. Treatment of these cells with the anti-GR agent mifepristone showed that they were more sensitive to this drug than enzalutamide, as were several of the enzalutamide non-responsive lines. This is consistent with several recent reports that suggest that GR expression is an alternative signaling mechanism that can bypass AR blockade. This study reinforces the utility of large cell line panels for the study of cancer and identifies several cell lines that represent ideal models to study AR-null cells that have upregulated GR to sustain growth.

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PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor

Cells ◽

10.3390/cells9010003 ◽

2019 ◽

Vol 9 (1) ◽

pp. 3

Author(s):

Magali Williamson ◽

Ritu Garg ◽

Claire M. Wells

Keyword(s):

Prostate Cancer ◽

Glucocorticoid Receptor ◽

Cancer Cells ◽

Androgen Deprivation Therapy ◽

Late Stage ◽

Nuclear Translocation ◽

Androgen Deprivation ◽

Nuclear Localization Sequence ◽

Prostate Cancer Cells ◽

Localization Sequence

Androgen receptor (AR) and glucocorticoid receptor (GR) are nuclear receptors whose function depends on their entry into the nucleus where they activate transcription of an overlapping set of genes. Both AR and GR have a role in resistance to androgen deprivation therapy (ADT), the mainstay of treatment for late stage prostate cancer. PlexinB1, a receptor for semaphorins, has been implicated in various cancers including prostate cancer and has a role in resistance to ADT. We show here that activation of PlexinB1 by Sema4D and Sema3C results in translocation of endogenous GR to the nucleus in prostate cancer cells, and that this effect is dependent on PlexinB1 expression. Sema4D/Sema3C promotes the translocation of GR-GFP to the nucleus and mutation of the nuclear localization sequence (NLS1) of GR abrogates this response. These findings implicate the importin α/β system in the Sema4D/Sema3C-mediated nuclear import of GR. Knockdown of PlexinB1 in prostate cancer cells decreases the levels of glucocorticoid-responsive gene products and antagonizes the decrease in cell motility and cell area of prostate cancer cells upon dexamethasone treatment, demonstrating the functional significance of these findings. These results show that PlexinB1 activation has a role in the trafficking and activation of the nuclear receptor GR and thus may have a role in resistance to androgen deprivation therapy in late stage prostate cancer.

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