New Insights in the Role of Androgen-to-Estrogen Ratios, Specific Growth Factors and Bone Cell Microenvironment to Potentiate Prostate Cancer Bone Metastasis

Prostate cancer progression to bone metastasis is an early event that remains dormant when the androgen ratio to estrogen is high. Only 40% of patients with bone metastasis and skeletal involvement survive past the first year. During andropause, changes in hormone ratios and nuclear receptor coregulator expression, in conjunction with crosstalk with fibroblast growth factors and bone stroma signaling pathways, reactivate the early metastasis. This review will provide insights into how this interplay induces changes in the osteolytic microenvironment to promote prostate cancer metastasis to the bone. While both AR and ER induce changes in the osteolytic microenvironment to promote bone metastasis, it is ERα overexpression that stimulates osteoblast differentiation, proliferation, osteoclast-mediated bone resorption, and the release of bone matrix factors. Loss of ERβ1 enhances VEGF expression and tumor cell survival through stimulation of osteoblast differentiation. Aberrant expression of FGFs and FGF receptors (FGFRs) initiates MAPK, PI3K, and PLCγ pathways, resulting in proliferation, dedifferentiation, angiogenesis and survival. The paracrine action of FGF10 may be required for bone metastasis reactivation due to interaction with bone stromal cells when E2/T ratio increases. This ratio change provides a potential mechanism for estrogen signal activation when prostate cancer cells express ERα in the presence of bone stromal cells, resulting in ERα predominance over the AR activity due to changes in coactivator/corepressor recruitment by ERα when circulating androgens are reduced during hormonal deprivation therapies

Nuclear Receptor Research: Contributions from Latin America

The fact that virtually every single aspect of cell function and the complex network of regulatory processes in an organism involve crucial roles by nuclear receptors is not surprising at the present time. Accordingly, thousands of studies are published every year in hundreds of journals with very broad spectra, making it difficult for researchers in the field to find specific information of interest to them. This is the reason why Nuclear Receptor Research was born; to gather in one journal most of the advances covering all facets of this cardinal group of regulatory transcription factors.Fil: Napimoga, Marcelo Henrique. São Leopoldo Mandic Institute and Research Center. Laboratory of Immunology and Molecular Biology; BrasilFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Migliorini Figueira, Ana Carolina. Brazilian Center for Research in Energy and Materials. Brazilian Biosciences National Laboratory; BrasilFil: Onate, Sergio A. . Universidad de Concepción; ChileFil: Castro Obregon, Susana. Universidad Nacional Autónoma de México. Instituto de Fisiología Celular; Méxic

The 1alpha,25-dihydroxy Vitamin D3 receptor preferentially recruits the coactivator SRC-1 during up-regulation of the osteocalcin gene

Binding of 1alpha,25-dihydroxy Vitamin D3 to the C-terminal domain (LBD) of its receptor (VDR), induces a conformational change that enables interaction of VDR with transcriptional coactivators such as the members of the p160/SRC family or the DRIP (Vitamin D interacting complex)/Mediator complex. These interactions are critical for VDR-mediated transcriptional enhancement of target genes. Recent reports indicate that nuclear receptors, including VDR, interact with p160/SRC members and the DRIP/Mediator complex in a sequential, cyclical, and mutually exclusive manner when bound to a target promoter, exhibiting also a high exchange rate. Here, we present an overview of how these coactivators are recruited to the bone-specific osteocalcin (OC) gene in response to short and long exposures to 1alpha,25-dihydroxy Vitamin D3. We find that in intact osteoblastic cells VDR and SRC-1 rapidly bind to the OC promoter in response to the ligand. This recruitment correlates with transcriptional enhancement of the OC gene and with increased histone acetylation at the OC promoter. In contrast, binding of the DRIP205 subunit, which anchors the DRIP/Mediator complex to the VDR, is detected at the OC promoter after several hours of incubation with 1alpha,25-dihydroxy Vitamin D3. Together, our results indicate that VDR preferentially recruits SRC-1 to enhance basal bone-specific OC gene transcription. We propose a model where specific protein-DNA and protein-protein interactions that occur within the context of the OC gene promoter in osteoblastic cells stabilize the preferential association of the VDR-SRC-1 complex

Phosphorylation at serine 208 of the 1alpha,25-dihydroxy Vitamin D3 receptor modulates the interaction with transcriptional coactivators

Upon ligand binding the 1alpha,25-dihydroxy Vitamin D3 receptor (VDR) undergoes a conformational change that allows interaction with coactivator proteins including p160/SRC family members and the multimeric DRIP complex through the DRIP205 subunit. Casein kinase II (CKII) phosphorylates VDR both in vitro and in vivo at serine 208 within the hinge domain. This phosphorylation does not affect the ability of VDR to bind DNA, but increases its ability to transactivate target promoters. Here, we have analyzed whether phosphorylation of VDR by CKII modulates the ability of VDR to interact with coactivators in vitro. We find that both mutation of serine 208 to aspartic acid (VDRS208D) or phosphorylation of VDR by CKII enhance the interaction of VDR with DRIP205 in the presence of 1alpha,25-dihydroxy Vitamin D3. We also find that the mutation VDRS208D neither affects the ability of this protein to bind DNA nor to interact with SRC-1 and RXRalpha. Together, our results indicate that phosphorylation of VDR at serine 208 contributes to modulate the affinity of VDR for the DRIP complex and therefore may have a role in vivo regulating VDR-mediated transcriptional enhancement