scholarly journals New Insights in Prostate Cancer Development and Tumor Therapy: Modulation of Nuclear Receptors and the Specific Role of Liver X Receptors

2018 ◽  
Vol 19 (9) ◽  
pp. 2545 ◽  
Author(s):  
Laura Bousset ◽  
Amandine Rambur ◽  
Allan Fouache ◽  
Julio Bunay ◽  
Laurent Morel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Tumor Therapy ◽  
Locally Advanced ◽  
Complementary Therapy ◽  
Liver X Receptors ◽  
Castration Resistant ◽  
Prostate Cancer Development ◽  
X Receptors

Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state in the vast majority of the cases, leading to questions about the molecular mechanisms involving the steroids and their respective nuclear receptors in this relapse. Interestingly, liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) have emerged as new actors in prostate physiology, beyond their historical roles of cholesterol sensors. More importantly LXRs have been proposed to be good pharmacological targets in PCa. This rational has been based on numerous experiments performed in PCa cell lines and genetic animal models pointing out that using selective liver X receptor modulators (SLiMs) could actually be a good complementary therapy in patients with a castration resistant PCa. Hence, this review is focused on the interaction among the androgen receptors (AR/NR3C4), estrogen receptors (ERα/NR3A1 and ERβ/NR3A2), and LXRs in prostate homeostasis and their putative pharmacological modulations in parallel to the patients’ support.

scholarly journals LXRs, SHP, and FXR in Prostate Cancer: Enemies or Ménage à Quatre With AR?

2018 ◽  
Vol 15 ◽  
pp. 155076291880107 ◽  
Author(s):  
Marica Cariello ◽  
Simon Ducheix ◽  
Salwan Maqdasy ◽  
Silvère Baron ◽  
Antonio Moschetta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nuclear Receptors ◽  
Cancer Progression ◽  
Prostate Cancer Cell ◽  
Farnesoid X Receptor ◽  
New Drugs ◽  
Liver X Receptors ◽  
Castration Resistance ◽  
Orphan Nuclear Receptors ◽  
X Receptors

Androgens and androgen receptor (AR, NR3C4) clearly play a crucial role in prostate cancer progression. Besides, the link between metabolic disorders and the risk of developing a prostate cancer has been emerging these last years. Interestingly, “lipid” nuclear receptors such as LXRα/NR1H3 and LXRβ/NR1H2 (as well as FXRα/NR1H4 and SHP/NR0B2) have been described to decrease the lipid metabolism, while AR increases it. Moreover, these former orphan nuclear receptors can regulate androgen levels and modulate AR activity. Thus, it is not surprising to find such receptors involved in the physiology of prostate. This review is focused on the roles of liver X receptors (LXRs), farnesoid X receptor (FXR), and small heterodimeric partner (SHP) in prostate physiology and their capabilities to interfere with the androgen-regulated pathways by modulating the levels of active androgen within the prostate. By the use of prostate cancer cell lines, mice deficient for these nuclear receptors and human tissue libraries, several authors have pointed out the putative possibility to pharmacologically target these receptors. These data open a new field of research for the development of new drugs that could overcome the castration resistance in prostate cancer, a usual phenomenon in patients.

scholarly journals ZRSR2 overexpression is a frequent and early event in castration-resistant prostate cancer development

2021 ◽  
Author(s):  
Haiqing He ◽  
Jun Hao ◽  
Xin Dong ◽  
Yu Wang ◽  
Hui Xue ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle Progression ◽  
Locally Advanced ◽  
Patient Treatment ◽  
Early Event ◽  
Driver Gene ◽  
Castration Resistant Prostate Cancer ◽  
Driver Genes ◽  
Castration Resistant ◽  
Pdx Models

Abstract Background Androgen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development. Methods We have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies. Results ZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway. Conclusion Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.

scholarly journals Characterization of Proteins Regulated by Androgen and Protein Kinase a Signaling in VCaP Prostate Cancer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1404
Author(s):  
Hye-Jin You ◽  
Byong-Chul You ◽  
Jong-Kwang Kim ◽  
Jae-Min Park ◽  
Bo-Seul Song ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Castration Resistant Prostate Cancer ◽  
Normal Prostate ◽  
Prostate Cancer Development ◽  
Kinase A

Androgen signaling via the androgen receptor (AR) is involved in normal prostate development and prostate cancer progression. In addition to androgen binding, a variety of protein kinases, including cyclic AMP-dependent protein kinase A (PKA), can activate the AR. Although hormone deprivation, especially that of androgen, continues to be an important strategy for treating prostate cancer patients, the disease ultimately progresses to castration-resistant prostate cancer (CRPC), despite a continuous hormone-deprived environment. To date, it remains unclear which pathways in this progression are active and targetable. Here, we performed a proteomic analysis of VCaP cells stimulated with androgen or forskolin to identify proteins specific for androgen-induced and androgen-bypassing signaling, respectively. Patterns of differentially expressed proteins were quantified, and eight proteins showing significant changes in expression were identified. Functional information, including a Gene Ontology analysis, revealed that most of these proteins are involved in metabolic processes and are associated with cancer. The mRNA and protein expression of selected proteins was validated, and functional correlations of identified proteins with signaling in VCaP cells were assessed by measuring metabolites related to each enzyme. These analyses offered new clues regarding effector molecules involved in prostate cancer development, insights that are supported by the demonstration of increased expression levels of the eight identified proteins in prostate cancer patients and assessments of the progression-free interval. Taken together, our findings show that aberrant levels of eight proteins reflect molecular changes that are significantly regulated by androgen and/or PKA signaling pathways, suggesting possible molecular mechanisms of CRPC.

scholarly journals Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Medicines ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 82 ◽  
Author(s):  
Ugo Testa ◽  
Germana Castelli ◽  
Elvira Pelosi
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Intraepithelial Neoplasia ◽  
Cancer Development ◽  
Initial Development ◽  
Therapeutic Implications ◽  
Cancer Pathways ◽  
Signaling Axis ◽  
Prostate Cancer Development ◽  
Prostate Cancers

Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

Abstract C16: Targeting AR in castration-resistant prostate cancer: Development of ARN-509 and second-generation antiandrogen resistance models

2012 ◽  
Vol 72 (4 Supplement) ◽  
pp. C16-C16
Author(s):  
James D. Joseph ◽  
Anna Aparicio ◽  
Josh Kaufman ◽  
Jackie Julien ◽  
Celine Bonnefous ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Second Generation ◽  
Cancer Development ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Prostate Cancer Development

Molecular mechanisms of plant steroids and study of their interaction with nuclear receptors in prostate cancer cells

2020 ◽  
Vol 137 ◽  
pp. 111164 ◽  
Author(s):  
Zlata Huskova ◽  
Jana Steigerova ◽  
Jana Oklestkova ◽  
Lucie Rarova ◽  
Zdenek Kolar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Prostate Cancer Cells

Evaluation of Docetaxel-Sensitive and Docetaxel-Resistant Proteomes in PC-3 Cells

2015 ◽  
Vol 95 (1) ◽  
pp. 114-119 ◽  
Author(s):  
Shulu Zu ◽  
Weiming Ma ◽  
Pan Xiao ◽  
Yazhou Cui ◽  
Tianjia Ma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Polyacrylamide Gel Electrophoresis ◽  
Acquired Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Ionization Time ◽  
Flight Mass Spectrometry ◽  
Docetaxel Resistance ◽  
Castration Resistant ◽  
Glucose Regulated Protein

Objectives: Docetaxel was the first drug with proven survival benefit in men with castration-resistant prostate cancer. Acquired resistance to docetaxel precedes fatality in castration-resistant prostate cancer. The aims of this study were to evaluate docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells, and to investigate the molecular mechanism of docetaxel-resistant PC-3 cells. Methods: Docetaxel-resistant PC-3 cells were developed by docetaxel dose escalation. The global profiling of the protein expression was investigated in docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells using 2-dimensional polyacrylamide gel electrophoresis/matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Results: Forty-nine differential proteins were found in docetaxel-resistant PC-3 cells in comparison with docetaxel-sensitive PC-3 cells. Expression in 29 proteins was upregulated, whereas expression in 20 proteins was downregulated. ATP synthase and galectin-1 were involved in the formation of tumor vessels; calreticulin, cathepsin D, and cofilin were involved in tumor metastasis, and GRP78 (78-kDa glucose-regulated protein) and microtubule-associated protein-6 were involved in drug resistance of tumor. Conclusion: It is suggested that a proteomic expression difference exists between docetaxel-sensitive and docetaxel-resistant PC-3 cells, which would be helpful for further understanding the molecular mechanisms of docetaxel resistance in PC-3 cells.

scholarly journals PD25-11 MULTIVISCERAL SURGERY IN MEN WITH LOCALLY ADVANCED, SYMPTOMATIC CASTRATION RESISTANT PROSTATE CANCER

2019 ◽  
Vol 201 (Supplement 4) ◽  
Author(s):  
Friederike Haidl* ◽  
David Pfister ◽  
Daniel Porres ◽  
Leonidas Karapanos ◽  
Johannes Salem ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Locally Advanced ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Multivisceral Surgery
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