Androgen Receptor Splice Variant AR3 Promotes Prostate Cancer via Modulating Expression of Autocrine/Paracrine Factors

Sun, Feng; Chen, He Ge; Li, Wei; Yang, Xi; Wang, Xin; Jiang, Richeng; Guo, Zhiyong; Chen, Hegang; Huang, Jiaoti; Borowsky, Alexander D.; Qiu, Yun

doi:10.1074/jbc.m113.492140

Cited by 78 publications

(76 citation statements)

References 60 publications

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“…They also found that increased mesenchymal signatures in prostate tumors from patients treated with androgen-deprivation therapy [16]. A recent study further suggest that AR3 driven PCa initiation and progression can occur in a transgenic mouse model (AR3Tg) by modulating TGF-beta pathway, which was associated with the elaboration of EMT signatures and increasing prostatic progenitor cell population [11]. These in vivo results confirmed our findings indicating that androgen deprivation-mediated increased expression of AR3 contributes to the development of CRPC and mCRPC by regulating EMT and stem cell pathways.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes

Kong

Sethi

et al. 2014

Prostate

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Background The mechanism(s) by which androgen receptor (AR) splice variants contribute to castration-resistant prostate cancer (CRPC) is still lacking. Methods Expressions of Epithelial-to-Mesenchymal Transition (EMT) and stem cell markers were molecularly tested using prostate cancer (PCa) cells transfected with AR and AR3 (also known as AR-V7) plasmids or siRNA, and also cultured cells under androgen deprivation therapy (ADT) condition. Cell migration, clonogenicity, sphere forming capacity was assessed using PCa cells under all experimental conditions and 3, 3′-diindolylmethane (DIM; BR-DIM) treatment. Human PCa samples from BR-DIM untreated or treated patients were also used for assessing the expression of AR3 and stem cell markers. Results Overexpression of AR led to the induction of EMT phenotype, while overexpression of AR3 not only induced EMT but also led to the expression of stem cell signature genes. More importantly, ADT enhanced the expression of AR and AR3 concomitant with up-regulated expression of EMT and stem cell marker genes. Dihydrotestosterone (DHT) treatment decreased the expression of AR and AR3, and reversed the expression of these EMT and stem cell marker genes. BR-DIM administered to PCa patients prior to radical prostatectomy inhibited the expression of cancer stem cell markers consistent with inhibition of self-renewal of PCa cells after BR-DIM treatment. Conclusion AR variants could contribute to PCa progression through induction of EMT and acquisition of stem cell characteristics, which could be attenuated by BR-DIM, suggesting that BR-DIM could become a promising agent for the prevention of CRPC and/or for the treatment of PCa

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Section: Discussionmentioning

confidence: 99%

Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes

Kong

Sethi

et al. 2014

Prostate

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“…AR-V expression is found to be common in tumor metastases; furthermore, levels of variant expression directly correlate with accelerated disease progression and shorter cancer-specific survival [36, 101]. Experiments on mice have shown that AR v567es can induce autonomous tumor formation and proliferation [54], and AR-V7 expression leads to the expression of tumor promoting growth factors such as TGFβ2 and IGF1 [83]. These findings suggest that AR-Vs are biologically significant and may contribute to clinical progression of prostate cancer.…”

Section: Androgen Receptor Splice Variantsmentioning

confidence: 99%

Androgen Receptor Splice Variants in the Era of Enzalutamide and Abiraterone

Nakazawa¹,

Antonarakis

Luo³

2014

HORM CANC

104

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The FDA approvals of enzalutamide and abiraterone have rapidly changed the clinical landscape of prostate cancer treatment. Both drugs were designed to further suppress androgen receptor (AR) signaling, which is restored following first-line androgen deprivation therapies. Resistance to enzalutamide and abiraterone, however, is again marked by a return of AR signaling, indicating a remarkable “addiction” of prostate cancer cells to the AR pathway. Several mechanisms of castration resistance have been uncovered in the past decades, featuring a wide spectrum of molecular alterations that may explain sustained AR signaling in castration-resistant prostate cancers (CRPC). Among these, the androgen receptor splice variants (AR-Vs), particularly variant 7 (AR-V7), have been implicated in resistance to enzalutamide and abiraterone in preclinical studies, and they cannot be targeted by currently available AR-directed drugs. Drug development for AR-V–associated CRPC may therefore be necessary to augment the preexisting treatment repertoire. In this mini-review, we will discuss general mechanisms of resistance to AR-directed therapies, with a focus on the role of androgen receptor splice variants in the new era of treating advanced prostate cancer with enzalutamide and abiraterone.

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“…However, the main mechanism of dexamethasone is unclear. In our previous study, modification of hormone affected the function of pericytes in prostate glands [2]. Under chronic inflammation, cytokines such as VEGF, IL17, induced transformation of cell types and neovascularization involving pericytes in periodontitis rats [3].…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Splice Variant AR3 Promotes Prostate Cancer via Modulating Expression of Autocrine/Paracrine Factors

Cited by 78 publications

References 60 publications

Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes

Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes

Androgen Receptor Splice Variants in the Era of Enzalutamide and Abiraterone

Dexamethasone Restores the Neovascularization of Spine Cord in Experimental Autoimmune Encephalomyelitis (EAE) Rodent Models

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