Androgen receptor splice variant 7 functions independently of the full length receptor in prostate cancer cells

Progression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized on the plasma membrane, possibly through palmitoylation of two cysteine residues within its unique C-terminal sequence. Mutation of these putative palmitoylation sites in AR8 led to loss of its plasma membrane localization. In addition, we demonstrated that overexpression of AR8 in prostate cancer cells promoted association of Src and AR with the EGF receptor in response to EGF treatment and enhanced tyrosine phosphorylation of AR. Conversely, specific knockdown of AR8 expression in prostate cancer cells compromised EGF-induced Src activation and AR phosphorylation. This effect was accompanied with attenuation of proliferation and increased apoptosis in prostate cancer cells cultured in androgen-depleted medium. We also showed that AR8 was required for optimal transcriptional activity of AR in response to treatment of both androgen and EGF. Taken together, our results demonstrate that the membrane-associated AR8 isoform may contribute to castration resistance by potentiating AR-mediated proliferative and survival responses to hormones and growth factors.

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Role of Circulating Tumor Cells (CTC), Androgen Receptor Full Length (AR-FL) and Androgen Receptor Splice Variant 7 (AR-V7) in a Prospective Cohort of Castration-Resistant Metastatic Prostate Cancer Patients

Cancers ◽

10.3390/cancers11091365 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1365 ◽

Cited By ~ 7

Author(s):

Carlo Cattrini ◽

Alessandra Rubagotti ◽

Linda Zinoli ◽

Luigi Cerbone ◽

Elisa Zanardi ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Splice Variant ◽

Full Length ◽

Lower Percentage ◽

Castration Resistant ◽

Psa Response ◽

Androgen Receptor Splice Variant

Background: Circulating tumor cells (CTC), androgen receptor full-length (AR-FL), and androgen receptor splice variant 7 (AR-V7) are prognostic in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). AR-V7 seems to predict resistance to androgen-receptor signaling inhibitors (ARSi). Methods: We assessed the association of CTC, AR-FL, and AR-V7 with prostate-specific antigen (PSA) response and overall survival (OS). We used a modified AdnaTest CTC-based AR-FL and AR-V7 mRNA assay. Chi-square test, Fisher Exact test, Kaplan–Meier method, log-rank test, Cox proportional hazards models were used as appropriate. Results: We enrolled 39 mCRPC pts, of those 24 started a first-line treatment for mCRPC (1L subgroup) and 15 had received at least two lines for mCRPC (>2L subgroup). CTC, AR-FL, and AR-V7 were enriched in >2L compared to 1L subgroup. Detection of these biomarkers was associated with a lower percentage of biochemical responses. Only 1/7 AR-V7+ pts had a PSA response and received cabazitaxel. Median OS was 4.7 months (95% CI 0.6–8.9) in AR-V7+ pts and not reached in AR-V7− pts. AR-V7 was the only variable with prognostic significance in the Cox model. Conclusion: AR-V7, CTC, and AR-FL are associated with advanced mCRPC and AR-V7+ predicts for shorter OS.

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Author Correction: Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells

Scientific Reports ◽

10.1038/s41598-021-90079-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Manjul Rana ◽

Jianrong Dong ◽

Matthew J. Robertson ◽

Paul Basil ◽

Cristian Coarfa ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Splice Variant ◽

Mrna Splicing ◽

Prostate Cancer Cells

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Abstract 1848: PPARγ function is attenuated by full length androgen receptor and the AR-V7 variant in human prostate cancer cells

10.1158/1538-7445.am2015-1848 ◽

2015 ◽

Author(s):

Emuejevoke Olokpa ◽

Lamonica V. Stewart

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Full Length ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells

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Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Cancers ◽

10.3390/cancers12071991 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1991 ◽

Cited By ~ 1

Author(s):

Carmen A. Banuelos ◽

Yusuke Ito ◽

Jon K. Obst ◽

Nasrin R. Mawji ◽

Jun Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Androgen Receptor ◽

Ionizing Radiation ◽

Cancer Cells ◽

Splice Variants ◽

Inhibitory Effect ◽

Full Length ◽

Brdu Incorporation ◽

Prostate Cancer Cells

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

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