New Hormonal Therapies for Castration-Resistant Prostate Cancer

Mostaghel, Elahe A.; Plymate, Stephen R.

doi:10.1016/j.ecl.2011.05.013

Cited by 20 publications

(16 citation statements)

References 72 publications

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“…This recurrent disease is termed as castration-resistant prostate cancer (CRPC). An interesting feature of CRPC is that, despite low levels of systemic androgen after castration, active AR signaling is maintained in these recurrent prostate cancers (Mostaghel & Plymate 2011). This has prompted several groups to search for mechanisms contributing to AR activation in the setting of low systemic androgen (Fig.…”

Section: Androgens and Ar In Prostate Development And Homeostasismentioning

confidence: 99%

Androgens and androgen receptor signaling in prostate tumorigenesis

Zhou¹,

Bolton²,

Jones³

2014

Journal of Molecular Endocrinology

164

112

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Androgens and androgen receptor (AR) signaling are necessary for prostate development and homeostasis. AR signaling also drives the growth of nearly all prostate cancer cells. The role of androgens and AR signaling has been well characterized in metastatic prostate cancer, where it has been shown that prostate cancer cells are exquisitely adept at maintaining functional AR signaling to drive cancer growth. As androgens and AR signaling are so intimately involved in prostate development and the proliferation of advanced prostate cancer, it stands to reason that androgens and AR are also involved in prostate cancer initiation and the early stages of cancer growth, yet little is known of this process. In this review, we summarize the current state of knowledge concerning the role of androgens and AR signaling in prostate tissue, from development to metastatic, castration-resistant prostate cancer, and use that information to suggest potential roles for androgens and AR in prostate cancer initiation.

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Section: Androgens and Ar In Prostate Development And Homeostasismentioning

confidence: 99%

Androgens and androgen receptor signaling in prostate tumorigenesis

Zhou¹,

Bolton²,

Jones³

2014

Journal of Molecular Endocrinology

164

112

View full text Add to dashboard Cite

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“…Additionally, abiraterone decreases the level of intratumoral androgens, which leads to increased AR splice variants (28). There have been more than 20 splice variants described; the most significant of which have an absent AR ligand binding domain, resulting in ligand-independent constitutive AR activation (20). When this occurs, traditional antiandrogens are no longer effective.…”

Section: Castration-resistant Disease Still Depends On Ar Signalingmentioning

confidence: 98%

“…Continued activation of AR signaling despite castration is critical in tumor progression (18,19), which is heralded by a rise in PSA and is one indicator of inappropriately restored or sustained AR function. This sustained function is thought to arise from multiple mechanisms such as AR amplification, increased sensitivity to low concentrations of circulating androgens, AR mutations, heightened production of AR coactivators, ligandindependent AR activation, enhanced local production of androgens, and alternative androgen sources (20).…”

Section: Castration-resistant Disease Still Depends On Ar Signalingmentioning

confidence: 99%

Androgen Deprivation Therapy as Primary Treatment for Prostate Cancer

Cannata¹,

Kirschenbaum

Levine³

2012

The Journal of Clinical Endocrinology & Metabolism

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Androgen deprivation therapy remains the treatment of choice for metastatic prostate cancer; however, it is not without its adverse effects, and most men with advanced disease eventually develop castration resistance. Newer compounds that more specifically and effectively target androgen and androgen receptor signaling in prostate cancer cells may provide more long-lasting remissions in advanced disease.

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“…In terms of therapeutic targeting NCOA1, one should keep in mind that carboxy-terminal-truncated AR proteins that occur as a result of aberrant splicing are frequently found in patients who experienced ADT failure and developed a castration-resistant state (Mostaghel & Plymate 2011). These constitutively active AR, such as the AR-V7 that is expressed, e.g.…”

Section: :6mentioning

confidence: 99%

The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1

Luef

Handle

Kharaishvili

et al. 2016

Endocrine-Related Cancer

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Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. [ 3 H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell line's AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

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New Hormonal Therapies for Castration-Resistant Prostate Cancer

Cited by 20 publications

References 72 publications

Androgens and androgen receptor signaling in prostate tumorigenesis

Androgens and androgen receptor signaling in prostate tumorigenesis

Androgen Deprivation Therapy as Primary Treatment for Prostate Cancer

The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1

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