scholarly journals Nuclear localization of parathyroid hormone-related peptide confers resistance to anoikis in prostate cancer cells

2012 ◽  
Vol 19 (3) ◽  
pp. 243-254 ◽  
Author(s):  
Serk In Park ◽  
Laurie K McCauley
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Parathyroid Hormone ◽  
Cancer Cells ◽  
Nuclear Localization ◽  
Molecular Mechanisms ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Related Peptide ◽  
Parathyroid Hormone Related Peptide

Prostate cancer remains a leading cause of cancer-related death in men, largely attributable to distant metastases, most frequently to bones. Despite intensive investigations, molecular mechanisms underlying metastasis are not completely understood. Among prostate cancer-derived factors, parathyroid hormone-related peptide (PTHrP), first discovered as an etiologic factor for malignancy-induced hypercalcemia, regulates many cellular functions critical to tumor growth, angiogenesis, and metastasis. In this study, the role of PTHrP in tumor cell survival from detachment-induced apoptosis (i.e. anoikis) was investigated. Reduction ofPTHLH(encoding PTHrP) gene expression in human prostate cancer cells (PC-3) increased the percentage of apoptotic cells when cultured in suspension. Conversely, overexpression of PTHrP protected prostate cancer cells (Ace-1 and LNCaP, both typically expressing low or undetectable basal PTHrP) from anoikis. Overexpression of nuclear localization signal (NLS)-defective PTHrP failed to protect cells from anoikis, suggesting that PTHrP-dependent protection from anoikis is an intracrine event. A PCR-based apoptosis-related gene array showed that detachment increased expression of theTNFgene (encoding the proapoptotic protein tumor necrosis factor-α) fourfold greater in PTHrP-knockdown PC-3 cells than in control PC-3 cells. In parallel,TNFgene expression was significantly reduced in PTHrP-overexpressing LNCaP cells, but not in NLS-defective PTHrP overexpressing LNCaP cells, when compared with control LNCaP cells. Subsequently, in a prostate cancer skeletal metastasis mouse model, PTHrP-knockdown PC-3 cells resulted in significantly fewer metastatic lesions compared to control PC-3 cells, suggesting that PTHrP mediated antianoikis events in the bloodstream. In conclusion, nuclear localization of PTHrP confers prostate cancer cell resistance to anoikis, potentially contributing to prostate cancer metastasis.

scholarly journals Androgen Regulation of Parathyroid Hormone-Related Peptide Production in Human Prostate Cancer Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 858-867 ◽  
Author(s):  
Helena Pizzi ◽  
Julienne Gladu ◽  
Luisa Carpio ◽  
Dengshun Miao ◽  
David Goltzman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parathyroid Hormone ◽  
Cancer Cells ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Related Peptide ◽  
Androgen Regulation ◽  
Parathyroid Hormone Related Peptide

scholarly journals The Impact of Ang-(1-9) and Ang-(3-7) on the Biological Properties of Prostate Cancer Cells by Modulation of Inflammatory and Steroidogenesis Pathway Genes

2020 ◽  
Vol 21 (17) ◽  
pp. 6227
Author(s):  
Kamila Domińska ◽  
Karolina Kowalska ◽  
Kinga Anna Urbanek ◽  
Dominika Ewa Habrowska-Górczyńska ◽  
Tomasz Ochędalski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Cells ◽  
Renin Angiotensin System ◽  
Biological Properties ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
M Cell ◽  
Pc3 Cells ◽  
The Impact

The local renin–angiotensin system (RAS) plays an important role in the pathophysiology of the prostate, including cancer development and progression. The Ang-(1-9) and Ang-(3-7) are the less known active peptides of RAS. This study examines the influence of these two peptide hormones on the metabolic activity, proliferation and migration of prostate cancer cells. Significant changes in MTT dye reduction were observed depending on the type of angiotensin and its concentration as well as time of incubation. Ang-(1-9) did not regulate the 2D cell division of either prostate cancer lines however, it reduced the size of LNCaP colonies formed in soft agar, maybe through down-regulation of the HIF1a gene. Ang-(3-7) increased the number of PC3 cells in the S phase and improved anchorage-independent growth as well as mobility. In this case, a significant increase in MKI67, BIRC5, and CDH-1 gene expression was also observed as well as all members of the NF-kB family. Furthermore, we speculate that this peptide can repress the proliferation of LNCaP cells by NOS3-mediated G2/M cell cycle arrest. No changes in expression of BIRC5 and BCL2/BAX ratio were observed but a decrease mRNA proapoptotic BAD gene was seen. In the both lines, Ang-(3-7) improved ROCK1 gene expression however, increased VEGF and NOS3 mRNA was only seen in the PC3 or LNCaP cells, respectively. Interestingly, it appears that Ang-(1-9) and Ang-(3-7) can modulate the level of steroidogenic enzymes responsible for converting cholesterol to testosterone in both prostate cancer lines. Furthermore, in PC3 cells, Ang-(1-9) upregulated AR expression while Ang-(3-7) upregulated the expression of both estrogen receptor genes. Ang-(1-9) and Ang-(3-7) can impact on biological properties of prostate cancer cells by modulating inflammatory and steroidogenesis pathway genes, among others.

scholarly journals MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

2019 ◽  
Author(s):  
Hannah Weber ◽  
Rachel Ruoff ◽  
Michael J. Garabedian
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Cells ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation ◽  
Cancer Growth ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Insight Into ◽  
Androgen Independent

AbstractAndrogen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19 LNCaP cells. We also examined H3K27 acetylation genome-wide. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 and genomic sites occupied by MED19 and AR are enriched for ELK1, a transcription factor that binds the AR N-terminus to promote select AR-target gene expression. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.Author summaryProstate cancer is one of the most common cancers worldwide, and androgen hormones are essential for prostate cancer growth. Androgens exert their effects through a protein called the androgen receptor (AR), which turns on and off genes that regulate prostate cancer growth. Powerful drugs that block AR action by lowering androgen levels – so-called androgen deprivation therapy - are used to treat prostate cancer patients, and these yield initial success in reducing tumor growth. However, over time, tumors circumvent androgen deprivation therapy and patients relapse; in many cases, this occurs because AR becomes re-activated. The factors responsible for re-activating AR and promoting growth under androgen deprivation are not well understood. Here, we demonstrate that a subunit of the Mediator transcriptional regulatory complex, called MED19, promotes growth of prostate cancer cells under low androgen conditions, mimicking the ability of tumors to grow under androgen deprivation in prostate cancer patients. MED19 promotes androgen-independent growth by working with a transcription factor that interacts with AR, called ELK1, to induce the expression of genes regulated by AR that promote prostate cancer growth. This study provides important insight into how prostate cancer cells can maintain growth under androgen deprivation through MED19.

scholarly journals MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

PLoS Genetics ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. e1008540
Author(s):  
Hannah Weber ◽  
Rachel Ruoff ◽  
Michael J. Garabedian
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Cells ◽  
Androgen Deprivation ◽  
Monoamine Oxidase A ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Cancer Cell Growth ◽  
Androgen Independence ◽  
Androgen Independent

Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19-overexpressing LNCaP cells. We also examined genome-wide H3K27 acetylation. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation, and genomic sites occupied by MED19 and AR are enriched for motifs associated with ELK1. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.

scholarly journals The Effects of Sodium Butyrate as a Histone Deacetylase Inhibitor on the Activation of Toll-Like Receptor 4 in Prostate Cancer Cells

2021 ◽  
Author(s):  
Asuman Deveci Ozkan ◽  
Gamze Guney Eskiler ◽  
Ozge Turna ◽  
Nur Kazan
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Histone Deacetylase ◽  
Sodium Butyrate ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Apoptotic Cell ◽  
Lncap Cells ◽  
Prostate Cancer Cells

Abstract I. Background: Prostate cancer is the most diagnosed cancer in men and the covalent acetylation and deacetylation of histone proteins by the histone deacetylase (HDAC) enzymes can be considered a novel therapeutic target in PCa cells. Sodium butyrate (NaBu) is one of the most studied HDAC inhibitor (HDACi) which is a promising potential anticancer drug. Toll-like receptors (TLRs) are expressed on prostate cells and TLR4 expression is increased in prostate cancer cells and HDACi alter TLR-inducible gene expressions. Therefore, we aimed to evaluate the effects of NaBu on TLR4 mediating signaling pathways in two different PCa cells (DU-145 and LNCaP) for the first time.II. Methods and Results: The cytotoxicity of NaBu in PCa cells was determined by WST-1 assay. Apoptotic effects of NaBu were analyzed by Annexin V and AO/PI assays. Subcellular localization of TLR4, IRF3 and NF-κB proteins was evaluated by IF assay. Our results showed that NaBu significantly inhibited the viability of PCa cells and increased the percentage of apoptotic cells (p<0.01). However, DU-145 cells were more sensitive to NaBu than LNCaP cells. Furthermore, NaBu can induce the cytoplasmic TLR4 and IRF3 expression in particularly DU-145 cells without affecting nuclear translocation of NF-kB in PCa cells.III. Conclusions: NaBu induces apoptotic cell death and regulated the TLR4/IRF3 signaling pathways in DU-145 cells but not in LNCaP cells. Therefore, PCa cells differentially responded to NaBu treatment due to probably AR status. Therefore, further investigations should be performed to assess the molecular mechanisms underlying cell response to NaBu-induced TLR-mediated signaling pathways in vitro and in vivo.

scholarly journals Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Navatha Shree Polavaram ◽  
Samikshan Dutta ◽  
Ridwan Islam ◽  
Arup K. Bag ◽  
Sohini Roy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Potential Effect ◽  
Tumor Burden ◽  
Bone Lesions ◽  
Prostate Cancer Cells

AbstractUnderstanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

Newly synthesized benzimidazoles inhibits vascular endothelial growth factor and matrix metalloproteinase-2 and -9 levels in prostate cancer cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Suleyman Ilhan ◽  
Gamze Dilekci ◽  
Adem Guner ◽  
Hakan Bektas
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Imidazole Ring ◽  
Matrix Metalloproteinase 2 ◽  
Benzimidazole Derivatives ◽  
Prostate Cancer Cells ◽  
Protein Levels ◽  
Umbilical Vein Endothelial Cells

Background: Investigating the effects of newly synthesized agents on various molecular mechanisms to understand their mechanism of action is an important step of pre-clinical screening. Benzimidazoles are composed of a unique fused benzene and imidazole ring and have attracted great attention due to their broad bioactivities, including antitumor. Objective: In the current study, we reported the synthesis of novel benzimidazole derivatives and investigated the possible cytotoxic and anti-angiogenic effects on human prostate cancer and umbilical vein endothelial cells (HUVECs). Methods: MTT assay was used to assess cell viability. A scratch assay was conducted to monitor the migration of cells. mRNA expression levels of VEGF, MMP-2, and MMP-9 were evaluated using qPCR. Changes in protein levels were evaluated by western blotting. Results: Compound G1, having a chlorine moiety, showed a potent cytotoxic activity on both prostate cancer cells and HUVECs, and inhibited cell migration via decreasing the mRNA and protein levels of key angiogenesis-related molecules such as VEGF, MMP-2, and MMP-9. Conclusion: These results suggest that newly synthesized G1 may be a novel anti-angiogenic agent for prostate cancer treatment.

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