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Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone.

ABSTRACT: Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERR?) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERR? expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERR? in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGF?1 were upregulated by ERR? in tumor cells and all of these factors also significantly and positively correlated withERR? expression in CRPC patient specimens. Finally, high levels of ERR? in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERR? regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERR? is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERR? may constitute a new therapeutic strategy for prostate cancer skeletal-related events.

SUBMITTER: Fradet A

PROVIDER: S-EPMC5363569 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone.

Fradet Anais A Bouchet Mathilde M Delliaux Carine C Gervais Manon M Kan Casina C Benetollo Claire C Pantano Francesco F Vargas Geoffrey G Bouazza Lamia L Croset Martine M Bala Yohann Y Leroy Xavier X Rosol Thomas J TJ Rieusset Jennifer J Bellahcène Akeila A Castronovo Vincent V Aubin Jane E JE Clézardin Philippe P Duterque-Coquillaud Martine M Bonnelye Edith E

Oncotarget 20161101 47

Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-fun ...[more]

PMID: 27776343

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Project description:BackgroundAs deregulation of androgen receptor (AR) signaling target genes is associated with tumorigenesis and the development of prostate cancer (PCa), AR signaling is the primary therapeutic target for PCa. Although patients initially responses to first-line androgen deprivation therapies (ADTs), most of them with advanced PCa progress to lethal castration-resistant prostate cancer (CRPC). Recent studies have suggested the molecular mechanisms by which AR elicit the robust up-regulation of the FKBP51 gene. We suggest that restored expression of FKBP51 gene, modulated by androgen receptor splicing variant 7 (AR-V7) which replaces full length androgen receptor (AR-FL) in androgen ablation status, promotes CRPC progression through activating NF-κB signaling.MethodsImmunohistochemistry assays were used to detect the expression of AR-V7, FKBP51 and NF-κB signaling correlated proteins in CRPC tissues. An androgen ablation resistant PCa cell line model established by Long-term culturing in androgen depleted medium, named androgen-independent LNCaP (LNCaP-AI) cells, were used to dynamically monitor FKBP51 expression during the process of androgen dependent PCa cells transforming into androgen-independent cells, as well as its association with NF-κB signal pathway. LNCaP-AI cell line was determined to express AR-V7 protein continuously. Luciferase reporter assays and DNA pull down were used to determine the association between AR-V7 and FKBP51.ResultsOur results suggested that CRPC patients with AR-V7 high expression tend to have higher expression of FKBP51 and enhanced NF-κB signaling compared with AR-V7 negative patients. Knockdown of AR-V7 or FKBP51 in LNCaP-AI cells attenuated the level of p-NF-κB (Ser536) and androgen-resistant cells growth. Luciferase reporter assays and DNA pull down results indicated that FKBP51 was transcriptionally promoted by AR-V7 in absence of androgen, which enhanced NF-κB signaling.ConclusionsBecause of upregulation of AR-V7 in androgen-independent PCa cells, increasing of FKBP51 induced NF-κB signaling, leading to progression of CRPC.

Dataset Information

Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone.

Publications

Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone.

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