Activation of retinoic acid receptor reduces metastatic prostate cancer bone lesions through blocking endothelial-to-osteoblast transition

Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that contribute to progression and therapy resistance. Currently strategies targeting PCa-induced bone formation are lacking. We previously showed that PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces PCa-induced bone formation. We found that palovarotene, a RARgamma agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralization in vitro, and decreased tumor-induced bone formation and tumor growth in several osteogenic PCa models. RARalpha, beta and gamma isoform knockdown in 2H11 ECs blocked EC-to-OSB transition and osteoblast mineralization. Pan-RAR agonist ATRA inhibited MycCaP-BMP4-induced bone formation and tumor growth under castration. Furthermore, palovarotene or ATRA reduced plasma Tenascin C, a factor secreted by EC-OSB cells, which may be used to monitor treatment response. Mechanistically, BMP4-activated pSmad1 forms a complex with RAR in the nucleus of 2H11 cells. RAR activation by palovarotene or ATRA causes pSmad1 degradation by recruiting E3-ubiquitin ligase Smurf1 into the nuclear pSmad1/RARgamma complex. Our findings suggest that palovarotene can be repurposed to target PCa-induced bone formation to improve clinical outcomes for bone metastasis.

Download Full-text

Human skin levels of retinoic acid and cytochrome P-450-derived 4-hydroxyretinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor-mediated transcription in vitro.

Journal of Clinical Investigation ◽

10.1172/jci115990 ◽

1992 ◽

Vol 90 (4) ◽

pp. 1269-1274 ◽

Cited By ~ 77

Author(s):

E A Duell ◽

A Aström ◽

C E Griffiths ◽

P Chambon ◽

J J Voorhees

Keyword(s):

Retinoic Acid ◽

Human Skin ◽

Topical Application ◽

Retinoic Acid Receptor ◽

Acid Receptor ◽

Transcription In Vitro ◽

Cytochrome P 450

Download Full-text

7025 Prognostic value of hypermethylation for retinoic acid receptor beta (RARB) and p-16 genes in patients with prostate cancer

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(09)71403-x ◽

2009 ◽

Vol 7 (2) ◽

pp. 414

Author(s):

A. Ameri ◽

M.H. Emranpour ◽

M.R. Abbaszadegan ◽

A. Alidoosti ◽

F. Taslimi ◽

...

Keyword(s):

Prostate Cancer ◽

Retinoic Acid ◽

Prognostic Value ◽

Retinoic Acid Receptor ◽

Acid Receptor ◽

Retinoic Acid Receptor Beta ◽

P 16 ◽

Receptor Beta

Download Full-text

Inhibitory effect of retinoic acid receptor agonists on in vitro chondrogenic differentiation

Anatomical Science International ◽

10.1007/s12565-019-00512-3 ◽

2019 ◽

Vol 95 (2) ◽

pp. 202-208

Author(s):

Yusuke Sumitani ◽

Kenta Uchibe ◽

Kaya Yoshida ◽

Yao Weng ◽

Jiajie Guo ◽

...

Keyword(s):

Retinoic Acid ◽

Chondrogenic Differentiation ◽

Retinoic Acid Receptor ◽

Inhibitory Effect ◽

Acid Receptor ◽

Receptor Agonists

Download Full-text

Effects of Vitamin-A Status on Hamster Tracheal Epithellum in Viva in Vitro

Food and Nutrition Bulletin ◽

10.1177/156482658901100304 ◽

1989 ◽

Vol 11 (3) ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Luigi M. De Luca ◽

Elizabeth M. McDowell

Keyword(s):

Retinoic Acid ◽

Vitamin A ◽

Retinoic Acid Receptor ◽

Normal Liver ◽

Acid Receptor ◽

New Horizons ◽

Vitamin A Status ◽

Essential Nutrient ◽

Hepatoma Tissue

In this paper we have suggested the new concept of exotrophic cells, i.e. cells that have conditionally escaped the need for an essential nutrient, such as vitamin A. These exotrophs might become fixed by a mutation and eventually contribute to the tumorigenic phenotype. The discovery of the retinoic acid receptor (RAR) has opened up new horizons in the search for the mechanism of action of retinoic acid [17; 18]. It is intriguing that a second retinoic acid receptor, RARE, is abundantly expressed in hepatoma tissue and not in normal liver; Benbrook et al. [191 suggest that the erroneous expression of the RARE might contribute to tumour development in liver. How and whether these findings relate to the vitamin-A-deficient status of hepatoma cells remains to be understood.

Download Full-text

Attenuation of Hypertrophy in Human MSCs via Treatment with a Retinoic Acid Receptor Inverse Agonist

International Journal of Molecular Sciences ◽

10.3390/ijms21041444 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1444 ◽

Cited By ~ 1

Author(s):

Moritz Riedl ◽

Christina Witzmann ◽

Matthias Koch ◽

Siegmund Lang ◽

Maximilian Kerschbaum ◽

...

Keyword(s):

Retinoic Acid ◽

Cell Fate ◽

Limb Development ◽

Retinoic Acid Receptor ◽

Cartilage Regeneration ◽

Inverse Agonist ◽

Cartilage Tissue ◽

Human Mscs ◽

Acid Receptor

In vitro chondrogenically differentiated mesenchymal stem cells (MSCs) have a tendency to undergo hypertrophy, mirroring the fate of transient “chondrocytes” in the growth plate. As hypertrophy would result in ossification, this fact limits their use in cartilage tissue engineering applications. During limb development, retinoic acid receptor (RAR) signaling exerts an important influence on cell fate of mesenchymal progenitors. While retinoids foster hypertrophy, suppression of RAR signaling seems to be required for chondrogenic differentiation. Therefore, we hypothesized that treatment of chondrogenically differentiating hMSCs with the RAR inverse agonist, BMS204,493 (further named BMS), would attenuate hypertrophy. We induced hypertrophy in chondrogenic precultured MSC pellets by the addition of bone morphogenetic protein 4. Direct activation of the RAR pathway by application of the physiological RAR agonist retinoic acid (RA) further enhanced the hypertrophic phenotype. However, BMS treatment reduced hypertrophic conversion in hMSCs, shown by decreased cell size, number of hypertrophic cells, and collagen type X deposition in histological analyses. BMS effects were dependent on the time point of application and strongest after early treatment during chondrogenic precultivation. The possibility of modifing hypertrophic cartilage via attenuation of RAR signaling by BMS could be helpful in producing stable engineered tissue for cartilage regeneration.

Download Full-text

Clinical Significance of Retinoic Acid Receptor Beta Promoter Methylation in Prostate Cancer: A Meta-Analysis

Cellular Physiology and Biochemistry ◽

10.1159/000488268 ◽

2018 ◽

Vol 45 (6) ◽

pp. 2497-2505 ◽

Cited By ~ 5

Author(s):

MengMeng Dou ◽

XueLiang Zhou ◽

ZhiRui Fan ◽

XianFei Ding ◽

LiFeng Li ◽

...

Keyword(s):

Prostate Cancer ◽

Retinoic Acid ◽

Promoter Methylation ◽

Subgroup Analysis ◽

Retinoic Acid Receptor ◽

Meta Analysis ◽

Source Region ◽

Acid Receptor ◽

Retinoic Acid Receptor Beta ◽

Receptor Beta

Background/Aims: Retinoic acid receptor beta (RAR beta) is a retinoic acid receptor gene that has been shown to play key roles during multiple cancer processes, including cell proliferation, apoptosis, migration and invasion. Numerous studies have found that methylation of the RAR beta promoter contributed to the occurrence and development of malignant tumors. However, the connection between RAR beta promoter methylation and prostate cancer (PCa) remains unknown. This meta-analysis evaluated the clinical significance of RAR beta promoter methylation in PCa. Materials and Methods: We searched all published records relevant to RAR beta and PCa in a series of databases, including PubMed, Embase, Cochrane Library, ISI Web of Science and CNKI. The rates of RAR beta promoter methylation in the PCa and control groups (including benign prostatic hyperplasia and normal prostate tissues) were summarized. In addition, we evaluated the source region of available samples and the methods used to detect methylation. To compare the incidence and variation in RAR beta promoter methylation in PCa and non-PCa tissues, the odds ratio (OR) and 95% confidence interval (CI) were calculated accordingly. All the data were analyzed with the statistical software STATA 12.0. Results: Based on the inclusion and exclusion criteria, 15 articles assessing 1,339 samples were further analyzed. These data showed that the RAR beta promoter methylation rates in PCa tissues were significantly higher than the rates in the non-PCa group (OR=21.65, 95% CI: 9.27-50.57). Subgroup analysis according to the source region of samples showed that heterogeneity in Asia was small (I2=0.0%, P=0.430). Additional subgroup analysis based on the method used to detect RAR beta promoter methylation showed that the heterogeneity detected by MSP (methylation-specific PCR) was relatively small (I2=11.3%, P=0.343). Conclusion: Although studies reported different rates for RAR beta promoter methylation in PCa tissues, the total analysis demonstrated that RAR beta promoter methylation may be correlated with PCa carcinogenesis and that the RAR beta gene is particularly susceptible. Additional studies with sufficient data are essential to further evaluate the clinical features and prognostic utility of RAR beta promoter methylation in PCa.

Download Full-text

Ligand-Activated Retinoic Acid Receptor Inhibits AP-1 Transactivation by Disrupting c-Jun/c-Fos Dimerization

Molecular Endocrinology ◽

10.1210/mend.13.2.0237 ◽

1999 ◽

Vol 13 (2) ◽

pp. 276-285 ◽

Cited By ~ 37

Author(s):

Xiao-Feng Zhou ◽

Xi-Qiang Shen ◽

Lirim Shemshedini

Keyword(s):

Retinoic Acid ◽

Dna Binding ◽

Transcriptional Activity ◽

Retinoic Acid Receptor ◽

Cellular Growth ◽

Dependent Manner ◽

Acid Receptor ◽

Retinoid Receptors ◽

Two Hybrid

Abstract In the presence of retinoic acid (RA), the retinoid receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), are able to up-regulate transcription directly by binding to RA-responsive elements on the promoters of responsive genes. Liganded RARs and RXRs are also capable of down-regulating transcription, but, by contrast, this is an indirect effect, mediated by the interaction of these nuclear receptors not with DNA but the transcription factor activating protein-1 (AP-1). AP-1 is a dimeric complex of the protooncoproteins c-Jun and c-Fos and directly regulates transcription of genes important for cellular growth. Previous in vitro results have suggested that RARs can block AP-1 DNA binding. Using a mammalian two-hybrid system, we report here that human RARα (hRARα) can disrupt in a RA-dependent manner the homo- and heterodimerization properties of c-Jun and c-Fos. This inhibition of dimerization is cell specific, occurring only in those cells that exhibit RA-induced repression of AP-1 transcriptional activity. Furthermore, this mechanism appears to be specific for the RARs, since another potent inhibitor of AP-1 activity, the glucocorticoid receptor, does not affect AP-1 dimerization. Our data argue for a novel mechanism by which RARs can repress AP-1 DNA binding, in which liganded RARs are able to interfere with c-Jun/c-Jun homodimerization and c-Jun/c-Fos heterodimerization and, in this way, may prevent the formation of AP-1 complexes capable of DNA binding.

Download Full-text