Functional Interaction between Rb and Thoc1 in Mouse Prostate Tumorigenesis

Androgen signaling via the androgen receptor (AR) transcription factor is crucial to normal prostate homeostasis and prostate tumorigenesis. Current models of AR function are predominantly based on studies of prostate-specific antigen regulation in androgen-responsive cell lines. To expand on these in vitro paradigms, we used the mouse prostate to elucidate the mechanisms through which AR regulates another direct target, FKBP5, in vivo. FKBP5 encodes an immunophilin that has been previously implicated in glucocorticoid and progestin signaling pathways and that likely influences prostate physiology in the presence of androgens. In this work, we show that androgens directly regulate FKBP5 via an interaction between the AR and a distal enhancer located 65 kb downstream of the transcription start site in the fifth intron of the FKBP5 gene. We have found that AR selectively recruits cAMP response element-binding protein to this enhancer. These interactions, in turn, result in chromatin remodeling that affects the enhancer proper but not the FKBP5 locus as a whole. Furthermore, in contrast to prostate-specific antigen-regulatory mechanisms, we show that transactivation of the FKBP5 gene does not rely on a single looping complex to mediate communication between the distal enhancer and proximal promoter. Rather, the distal enhancer complex and basal transcription apparatus communicate indirectly with one another, implicating a regulatory mechanism that has not been previously appreciated for AR target genes.

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Different effects of corticotropin-releasing factor and urocortin 2 on apoptosis of prostate cancer cells in vitro

Journal of Molecular Endocrinology ◽

10.1530/jme-11-0048 ◽

2011 ◽

Vol 47 (2) ◽

pp. 219-227 ◽

Cited By ~ 16

Author(s):

Lai Jin ◽

Qichun Zhang ◽

Rui Guo ◽

Lina Wang ◽

Juejin Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Line ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Corticotropin Releasing Factor ◽

Akt Inhibitor ◽

Creb Phosphorylation ◽

Prostate Tumorigenesis ◽

Mouse Prostate

Urocortin (Ucn), a corticotropin-releasing factor (CRF)-related neuropeptide binding both CRF type 1 receptor (CRFR1) and CRFR2, has recently been found in prostate cancer. However, no report has yet been known to elucidate the roles of Ucn in prostate cancer via the two receptors. In this study, the expression of both CRFR1 and CRFR2 in the mouse prostate cancer cell line RM-1 were detected and cellular apoptosis was monitored in the presence of CRF or Ucn2, the CRFR1- and CRFR2-selective agonist respectively. CRF promoted apoptosis while Ucn2 exerted the opposite effect. CRF reduced Bcl-2 expression, induced Bax expression, and hyperpolarized the mitochondrial membrane potential to activate caspase-9. On the contrary, Ucn2 increased Bcl-2 expression and decreased Bax expression, in which phosphorylation of Akt and cyclic AMP response element-binding (CREB) was involved. Pretreatment with phosphatidylinositide 3-kinase/Akt inhibitor (LY-294002) prior to Ucn2 led to downregulation of CREB phosphorylation and hence reduced Bcl-2 expression. These effects of CRF and Ucn2 were abolished by antalarmin (Anta) and antisauvagine-30, the CRFR1- and CRFR2-selective antagonist respectively. In LNCaP cell line, similar effects on cell apoptosis by CRF and Ucn2 were observed. In summary, our results demonstrated CRFR1 and CRFR2 expression in prostate cancer and indicated the opposite apoptotic roles of the two different CRFRs. These data may contribute to uncovering the pathophysiological function of endogenous Ucn in prostate tumorigenesis and progression.

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Host versus cell-dependent effects of β-Arrestin-1 expression in prostate tumorigenesis

Carcinogenesis ◽

10.1093/carcin/bgab021 ◽

2021 ◽

Author(s):

Timothy O Adekoya ◽

Nikia Smith ◽

Ariel J Thomas ◽

Tonya S Lane ◽

Nija Burnette ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Receptor Expression ◽

Androgen Independence ◽

Prostate Tumorigenesis ◽

Akt Phosphorylation ◽

Mouse Prostate ◽

Cancer Aggressiveness ◽

Prostate Cancer Development

Abstract Prostate cancer constitutes a serious health challenge and remains one of the main causes of cancer-related death among men. The more aggressive form of the disease has been attributed to androgen independence; resulting in lack of response to androgen deprivation therapy and sustained activation of other growth pathways. The scaffold proteins β-arrestin 1 and 2 (βarr1 and βarr2) which are known to mediate G protein-coupled receptor desensitization and internalization, were also shown to modulate prostate tumorigenesis. βarr1 is significantly overexpressed (>4 fold) in prostate cancer cells relative to βarr2. In this study, we investigated the effect of βarr1 overexpression in prostate cancer development and progression using the mouse and human PCa cell xenografts, and autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) models deficient in β-arrestins Depletion of βarr1 in TRAMP mice (TRAMP/βarr1 -/-) increased PCa growth and decreased overall survival relative to control TRAMP or TRAMP/βarr2 -/- animals. Prostate tissues from TRAMP/βarr1 -/- tumors displayed an increase in androgen receptor expression whereas overexpression of βarr1 in TRAMP-C1 (TRAMP-C1-βarr1-GFP) which derived from TRAMP decreased AR expression, cell proliferation and tumor growth in nude mice xenografts, relative to control TRAMP-C1-GFP. Knockdown of βarr1 expression in human MDA PCa 2b cells (MDA PCa 2b-βarr1 -/-) also decreased AR expression cell proliferation and tumor growth relative to control (MDA PCa 2b-Sham) cells. Interestingly, both TRAMP-C1-βarr1-GFP and MDA PCa 2b-βarr1 -/- xenografts showed a decrease in AKT phosphorylation, but an increase MAPK activation. Altogether, the data indicate that the effect of βarr1 in modulating AR signaling to regulate prostate cancer aggressiveness is cell and host autonomous.

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Quercetin–Resveratrol Combination for Prostate Cancer Management in TRAMP Mice

Cancers ◽

10.3390/cancers12082141 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2141 ◽

Cited By ~ 3

Author(s):

Chandra K. Singh ◽

Gagan Chhabra ◽

Mary A. Ndiaye ◽

Imtiaz A. Siddiqui ◽

Jennifer E. Panackal ◽

...

Keyword(s):

Prostate Cancer ◽

Gene Networks ◽

Pcr Array ◽

Prostate Tumorigenesis ◽

Cancer Management ◽

Mouse Prostate ◽

Tumor Tissues ◽

Apoptosis Markers ◽

Vasculogenesis And Angiogenesis ◽

Induced Apoptosis

Prostate Cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men. Therefore, novel mechanistically-driven approaches are needed for PCa management. Here, we determined the effects of grape antioxidants quercetin and/or resveratrol (60 and 600 mg/kg, respectively, in diet) against PCa in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP)-model in prevention and intervention settings. We found resveratrol alone and in combination significantly inhibited prostate tumorigenesis in prevention setting, while the same was seen only in combination after intervention. The observed effects were associated with marked inhibition in proliferation, oxidative stress, and tumor survival markers, and induced apoptosis markers. Utilizing PCa PCR array analysis with prevention tumor tissues, we identified that quercetin–resveratrol modulates genes involved in promoter methylation, cell cycle, apoptosis, fatty acid metabolism, transcription factors, androgen response, PI3K/AKT and PTEN signaling. Ingenuity Pathway Analysis (IPA) identified IGF1 and BCL2 as central players in two gene networks. Functional annotation predicted increased apoptosis and inhibited cell viability/proliferation, hyperplasia, vasculogenesis, and angiogenesis with dual treatment. Furthermore, IPA predicted upstream inhibition of major PCa signaling VEGF, Ca2+, PI3K, CSF2, PTH). Based on PCR array, we identified decreased levels of EGFR, EGR3, and IL6, and increased levels of IGFBP7 and NKX3.1, overall supporting anti-PCa effects of quercetin–resveratrol.

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Establishment of An Orthotopic Prostate Cancer Xenograft Mouse Model Using Microscope-Guided Orthotopic Injection of LNCaP Cells Into The Dorsal Lobe of The Mouse Prostate

10.21203/rs.3.rs-299761/v1 ◽

2021 ◽

Author(s):

Weiyong Liu ◽

Yunkai Zhu ◽

Lei Ye ◽

Yajuan Zhu ◽

Yuhao Wang

Keyword(s):

Prostate Cancer ◽

Mouse Model ◽

Ultrasound Imaging ◽

Athymic Nude Mouse ◽

Lncap Cells ◽

Nude Mouse Model ◽

Prostate Tumorigenesis ◽

Mouse Prostate ◽

The Individual

Abstract Background: Orthotopic LNCaP xenograft mouse models closely mimic the progression of androgen-dependent prostate cancer in humans; however, orthotopic injection of LNCaP cells into the mouse prostate remains a challenge.Methods: Under the guidance of a stereoscopic microscope, the anatomy of the individual prostate lobes in male Balb/c athymic nude mice was investigated, and LNCaP cells were inoculated into the mouse dorsal prostate (DP) to generate orthotopic tumors that mimicked the pathophysiological process of prostate cancer in humans. Real-time ultrasound imaging was used to monitor orthotopic prostate tumorigenesis, contrast-enhanced ultrasonography (CEUS) was used to characterize tumor angiogenesis, and macroscopic and microscopic characteristics of tumors were described.Results: The DP had a trigonal bipyramid-shape and were located at the base of the seminal vesicles. After orthotopic inoculation, gray scale ultrasound imaging showed progressive changes in tumor echotexture, shape and location, and tumors tended to protrude into the bladder. After 8 weeks, the tumor take rate was 65% (n= 13/20 mice). On CEUS, signal intensity increased rapidly, peaked, and decreased gradually. Observations of gross specimens showed orthotopic prostate tumors were well circumscribed, round, dark brown, and soft, with a smooth outer surface and a glossy appearance. Microscopically, tumor cells were arranged in acini encircled by fibrous septa with variably thickened walls, mimicking human adenocarcinoma.Conclusions: This study describes a successful approach to establishing an orthotopic LNCaP xenograft Balb/c athymic nude mouse model. The model requires a thorough understanding of mouse prostate anatomy and proper technique. The model represents a valuable tool for the in vivo study of the biological processes involved in angiogenesis in prostate cancer and preclinical evaluations of novel anti-angiogenic therapies.

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