AR-V7 and prostate cancer: The watershed for treatment selection?

Ciccarese, Chiara; Santoni, Matteo; Brunelli, Matteo; Buti, Sebastiano; Modena, Alessandra; Nabissi, Massimo; Artibani, Walter; Martignoni, Guido; Montironi, Rodolfo; Tortora, Giampaolo; Massari, Francesco

doi:10.1016/j.ctrv.2015.12.003

Cited by 54 publications

(34 citation statements)

References 82 publications

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“…Based on the known antiangiogenic properties of ES and on more interesting evidence that human prostate endothelial cells also express AR (41, 42), the application of ES in combination therapies could synergize tumoristatic and tumoricidal effects with minimal resistance. Regarding the recent concerns about the acquired resistance to second‐line therapy using enzalutamide and abiraterone, due to GR up‐regulation and the emergence of AR splice variants in patients with CRPC (2, 8, 37), our study further provides a rationale to clinically validate the antitumor activity of ES overcoming resistance to current AR‐directed therapies, especially in a disease signature associated with GR up‐regulation as a compensatory mechanism.…”

Section: Discussionmentioning

confidence: 93%

“…These results are in line with earlier observations that antioxidant SOD mimetics suppress CRPC growth (14). It is also noteworthy that the emergence of the AR‐V7 splice variant in patients with CRPC is a newly identified resistance phenotype against enzalutamide and abiraterone therapies (8, 37). Our data demonstrate that ES treatment reduced both AR and AR‐V7 in 22Rv1 cells, suggesting that ES not only prevents conversion to androgen‐independent growth but that it also directly suppresses proliferation of cells that have already established androgen‐independent phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Endostatin inhibits androgen‐independent prostate cancer growth by suppressing nuclear receptor‐mediated oxidative stress

et al. 2017

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Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to reactivation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa. Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR) and downstream pro-oxidant signaling. This reversal after ES treatment significantly decreased PCa cell proliferation through down-regulation of GR and up-regulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant up-regulation of enzymes in the major reactive oxygen species (ROS) scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase, and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented the antioxidant system through up-regulation of glucose influx, the pentose phosphate pathway, and NAD salvaging pathways. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced resistant phenotype upon AR antagonism and that the dual targeting action of ES on AR and GR can be further translated to PCa therapy.-Lee, J. H., Kang, M., Wang, H., Naik, G., Mobley, J. A., Sonpavde, G., Garvey, W. T., Darley-Usmar, V. M., Ponnazhagan, S. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Endostatin inhibits androgen‐independent prostate cancer growth by suppressing nuclear receptor‐mediated oxidative stress

et al. 2017

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“…In contrast, AR-V7 protein is encoded by AR variant composed of exons 1, 2, and 3 and a cryptic exon termed exon 3B or cryptic exon 3 (CE3), which is generated by alternative use of the cryptic 3' SS in intron 3 ( Figure 3B). The resultant AR-V7 protein includes the NTD and DBD, but lacks the hinge region and LBD [72,73]. The AR-V7 protein is constitutively active and forms a heterodimer with the full-length AR protein, leading to the androgen-independent activation of canonical AR signaling.…”

Section: Psfmentioning

confidence: 99%

“…The AR-V7 protein is constitutively active and forms a heterodimer with the full-length AR protein, leading to the androgen-independent activation of canonical AR signaling. Moreover, the AR-V7 protein is indicated to form homodimer and regulate a unique set of genes [72,73]. PSF is suggested to regulate the splicing events that produce the full-length AR and AR-V7 variant.…”

Section: Psfmentioning

confidence: 99%

Roles of Splicing Factors in Hormone-Related Cancer Progression

Takeiwa

Mitobe

Ikeda

et al. 2020

IJMS

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Splicing of mRNA precursor (pre-mRNA) is a mechanism to generate multiple mRNA isoforms from a single pre-mRNA, and it plays an essential role in a variety of biological phenomena and diseases such as cancers. Previous studies have demonstrated that cancer-specific splicing events are involved in various aspects of cancers such as proliferation, migration and response to hormones, suggesting that splicing-targeting therapy can be promising as a new strategy for cancer treatment. In this review, we focus on the splicing regulation by RNA-binding proteins including Drosophila behavior/human splicing (DBHS) family proteins, serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) in hormone-related cancers, such as breast and prostate cancers.

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“…Each drug has enhanced the median survival of patients with lethal castrate-resistant metastatic disease by months and in the case of some individuals by years. In other cases however responses have been significantly less impressive due to a range of resistance mechanisms that include the expression of AR splice variants that lack a ligand-binding domain (for example AR-V7) (Ciccarese, Santoni, Brunelli et al, 2016), AR copy number amplification (Visakorpi, Hyytinen, Koivisto et al, 1995) and over-expression and the evolution of a dependency on other oncogenic signaling pathways driven by phosphatidyl inositol 3-kinase/Akt (PI3- Table 1). Therefore, BRD-containing proteins are transcriptional regulators that initiate chromatin re-shaping in order to prepare for transcription.…”

Section: Prostate Cancer the Ar Signaling Axis Chromatin And Bromomentioning

confidence: 99%

Bromodomain-containing proteins in prostate cancer

Urbanucci

Mills

2018

Molecular and Cellular Endocrinology

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Several oncogenic factors have been involved in prostate cancer progression. However, therapeutic approaches still focus on suppression of androgen receptor (AR) signaling. In fact, whereas the full-length AR incorporates a ligand-binding domain, which has become a drug target for competitive inhibitors, other transcription factors often do not have tractable binding pockets that aid drug development. Consequently drug development efforts have turned to transcription co-regulators, often chromatin-modifying enzymes or factors that bind to epigenetic modifications to chromatin. Bromodomain (BRD)-containing proteins fall into the latter category and significant progress has been made in developing small molecule inhibitors that target a particular subgroup of BRD-containing proteins known as the Bromodomain and extra-terminal (BET) family proteins. These inhibitors have proven particularly effective in inactivating c-Myc in lymphoma but more recently members of the BET family have also been identified as AR-interacting proteins raising the prospect of using these inhibitors as an alternative strategy for targeting AR-driven cancers. In this review we will provide an overview of BRD-containing proteins and the potential for exploiting them as biomarkers and drug targets in prostate cancer.

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AR-V7 and prostate cancer: The watershed for treatment selection?

Cited by 54 publications

References 82 publications

Endostatin inhibits androgen‐independent prostate cancer growth by suppressing nuclear receptor‐mediated oxidative stress

Endostatin inhibits androgen‐independent prostate cancer growth by suppressing nuclear receptor‐mediated oxidative stress

Roles of Splicing Factors in Hormone-Related Cancer Progression

Bromodomain-containing proteins in prostate cancer

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