mRNA expressions of androgen receptor and its variants in matched hormone-sensitive and castration-resistant prostate cancer

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

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Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer

The Prostate ◽

10.1002/pros.23248 ◽

2016 ◽

Vol 77 (1) ◽

pp. 60-71 ◽

Cited By ~ 5

Author(s):

Chan Ho Lee ◽

Ja Yoon Ku ◽

Jung Min Ha ◽

Sun Sik Bae ◽

Jeong Zoo Lee ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Castration Resistant Prostate Cancer ◽

Transcript Levels ◽

Castration Resistant ◽

Ubiquitin Conjugating Enzyme ◽

Hormone Sensitive ◽

Conjugating Enzyme

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COBLL1 modulates cell morphology and facilitates androgen receptor genomic binding in advanced prostate cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1721957115 ◽

2018 ◽

Vol 115 (19) ◽

pp. 4975-4980 ◽

Cited By ~ 3

Author(s):

Ken-ichi Takayama ◽

Takashi Suzuki ◽

Tetsuya Fujimura ◽

Satoru Takahashi ◽

Satoshi Inoue

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Progression ◽

Actin Binding ◽

Castration Resistant Prostate Cancer ◽

Cell Growth And Migration ◽

Castration Resistant ◽

Hormone Sensitive ◽

And Migration ◽

Cancer Tissues

Androgen receptor (AR) signaling is essential for prostate cancer progression and acquiring resistance to hormone therapy. However, the molecular pathogenesis through AR activation has not been fully understood. We performed integrative transcriptomic analysis to compare the AR program in a castration-resistant prostate cancer (CRPC) model with that in their parental hormone-sensitive cells. We found that the gene cordon-bleu–like 1 (COBLL1) is highly induced by AR in CRPC model cells. The expression of COBLL1 that possesses an actin-binding domain is up-regulated in clinical prostate cancer tissues and is associated with a poor prognosis for prostate cancer patients. COBLL1 is involved in the cancer cell morphogenesis to a neuron-like cell shape observed in the CRPC model cells, promoting cell growth and migration. Moreover, nuclear COBLL1 interacts with AR to enhance complex formation with CDK1 and facilitates AR phosphorylation for genomic binding in CRPC model cells. Thus, our findings showed the mechanistic relevance of cordon-bleu proteins during the AR-mediated progression to CRPC.

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Biomarkers of Castrate Resistance in Prostate Cancer: Androgen Receptor Amplification and T877A Mutation Detection by Multiplex Droplet Digital PCR

Journal of Clinical Medicine ◽

10.3390/jcm11010257 ◽

2022 ◽

Vol 11 (1) ◽

pp. 257

Author(s):

Francis P. Young ◽

Therese M. Becker ◽

Mohammed Nimir ◽

Thomas Opperman ◽

Wei Chua ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Splice Variants ◽

Point Mutations ◽

Digital Pcr ◽

Droplet Digital Pcr ◽

Castration Resistant Prostate Cancer ◽

Liquid Biopsies ◽

Castration Resistant ◽

Hormone Sensitive

Androgen Receptor (AR) alterations (amplification, point mutations, and splice variants) are master players in metastatic castration resistant prostate cancer (CRPC) progression and central therapeutic targets for patient management. Here, we have developed two multiplexed droplet digital PCR (ddPCR) assays to detect AR copy number (CN) and the key point mutation T877A. Overcoming challenges of determining gene amplification from liquid biopsies, these assays cross-validate each other to produce reliable AR amplification and mutation data from plasma cell free DNA (cfDNA) of advanced prostate cancer (PC) patients. Analyzing a mixed PC patient cohort consisting of CRPC and hormone sensitive prostate cancer (HSPC) patients showed that 19% (9/47) patients had AR CN amplification. As expected, only CRPC patients were positive for AR amplification, while interestingly the T877A mutation was identified in two patients still considered HSPC at the time. The ddPCR based analysis of AR alterations in cfDNA is highly economic, feasible, and informative to provide biomarker detection that may help to decide on the best follow-up therapy for CRPC patients.

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Faculty Opinions recommendation of Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.714997806.790402827 ◽

2012 ◽

Author(s):

Hendrik van Poppel ◽

Yuri Tolkach

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Splice Variants ◽

Castration Resistant Prostate Cancer ◽

Cancer Induction ◽

Castration Resistant ◽

Androgen Receptor Splice Variants

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Faculty Opinions recommendation of The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717970262.793478880 ◽

2013 ◽

Author(s):

Andrew D Sharrocks

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Castration Resistant Prostate Cancer ◽

Transcriptional Program ◽

Castration Resistant

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AR Copy Number and AR Signaling-directed Therapies in Castrationresistant Prostate Cancer

Current Cancer Drug Targets ◽

10.2174/1568009617666171122145852 ◽

2018 ◽

Vol 18 (9) ◽

pp. 869-876

Author(s):

Samanta Salvi ◽

Vincenza Conteduca ◽

Cristian Lolli ◽

Sara Testoni ◽

Valentina Casadio ◽

...

Keyword(s):

Prostate Cancer ◽

Copy Number ◽

Clinical Trial Design ◽

Complete Information ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Anti Cancer ◽

Hormone Sensitive ◽

Predictive And Prognostic Biomarker

Background: Adaptive upregulation of Androgen Receptor (AR) is the most common event involved in the progression from hormone sensitive to Castration-Resistant Prostate Cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. Objective: In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR Copy Number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Conclusion: Outcomes of CRPC patients are reported to be highly variable as the consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design.

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Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20092066 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2066 ◽

Cited By ~ 12

Author(s):

Namrata Khurana ◽

Suresh C. Sikka

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Signaling Pathways ◽

Critical Role ◽

Castration Resistant Prostate Cancer ◽

Form Complex ◽

Androgen Receptor Signaling ◽

Castration Resistant ◽

Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

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