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Restoration of FKBP51 protein promotes the progression of castration resistant prostate cancer.

ABSTRACT: Background:As 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-?B signaling. Methods:Immunohistochemistry assays were used to detect the expression of AR-V7, FKBP51 and NF-?B 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-?B 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. Results:Our results suggested that CRPC patients with AR-V7 high expression tend to have higher expression of FKBP51 and enhanced NF-?B signaling compared with AR-V7 negative patients. Knockdown of AR-V7 or FKBP51 in LNCaP-AI cells attenuated the level of p-NF-?B (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-?B signaling. Conclusions:Because of upregulation of AR-V7 in androgen-independent PCa cells, increasing of FKBP51 induced NF-?B signaling, leading to progression of CRPC.

SUBMITTER: Yu J

PROVIDER: S-EPMC6990039 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Restoration of FKBP51 protein promotes the progression of castration resistant prostate cancer.

Yu Jianpeng J Sun Libin L Hao Tangxi T Zhang Boya B Chen Xuanrong X Li Hanlin H Zhang Zheng Z Zhu Shimiao S Quan Changyi C Niu Yuanjie Y Shang Zhiqun Z

Annals of translational medicine 20191201 23

<h4>Background</h4>As 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-regulat ...[more]

PMID: 32042745

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Project description:Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12-18 months. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-kappaB activation supports its growth. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IkappaB kinase (IKK)-beta and its target NF-kappaB have important tumour-promoting functions within malignant cells and inflammatory cells. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-alpha, which stimulates metastasis by an NF-kappaB-independent, cell autonomous mechanism. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-beta activation results in production of cytokines that activate IKK-alpha and STAT3 in CaP cells to enhance hormone-free survival.

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Restoration of FKBP51 protein promotes the progression of castration resistant prostate cancer.

Publications

Restoration of FKBP51 protein promotes the progression of castration resistant prostate cancer.

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