Biologic activity of LSD1 inhibition by novel tranylcypromine structural analogues in prostate cancer cells.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 82-82
Author(s):  
Simon J. Crabb ◽  
Annette L Hayden ◽  
Rosemary A Strivens ◽  
Hanae Benelkebir ◽  
A Ganesan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Specific Antigen ◽  
Histone H3 ◽  
Prostate Cancer Cells ◽  
Poor Prognostic Factor ◽  
Structural Analogues ◽  
Chemical Inhibition

82 Background: Hormonal strategies to inhibit androgen receptor (AR) signalling remain inadequate and so novel approaches are urgently required. Lysine (K)-specific demethylase 1A (LSD1), is an epigenetic AR co-activator which modifies chromatin structure through de-methylation of histone H3 lysine 9 at androgen response elements to activate transcriptional expression of AR target genes. LSD1 is over-expressed and a poor prognostic factor in prostate cancer. We have synthesised novel analogues of the monoamine oxidase (MAO) inhibitor tranylcypromine as LSD1 inhibitors to exploit MAO and LSD1 sequence homology. Methods: We utilised prostate cancer cell line models to investigate the biological effect of LSD1 inhibition using tranylcypromine analogues. Results: Chemical inhibition of LSD1 was effective in inhibiting cell proliferation in prostate cancer models with around 1000 fold greater potency for synthesised analogues over tranylcypromine in LNCaP prostate cancer cells. Chemical inhibition of LSD1 induced the predicted histone methylation changes consequent on LSD1 inhibition of mono- and di-methylation of histone H3 lysine 9. In addition LSD1 depletion, AR depletion and reduced expression of the AR target gene prostate-specific antigen was demonstrated. Fractional effect assays demonstrated synergistic interactions in cell proliferation assays for tranylcypromine analogues with the androgen receptor antagonists bicalutamide and MDV3100. Conclusions: Our data demonstrate biological activity of LSD1 inhibition in prostate cancer cells with depletion of AR signalling using optimised structural analogues of established drugs for non-cancer indications. Therapeutic targeting of LSD1 for prostate cancer would represent a novel therapeutic paradigm for this disease.

scholarly journals Expression and Function of Lysophosphatidic Acid LPA1 Receptor in Prostate Cancer Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4883-4892 ◽  
Author(s):  
Rishu Guo ◽  
Elizabeth A. Kasbohm ◽  
Puneeta Arora ◽  
Christopher J. Sample ◽  
Babak Baban ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Lysophosphatidic Acid ◽  
Cell Cycle Progression ◽  
Receptor Activation ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
And Migration

The bioactive phospholipid lysophosphatidic acid (LPA) promotes cell proliferation, survival, and migration by acting on cognate G protein-coupled receptors named LPA1, LPA2, and LPA3. We profiled gene expression of LPA receptors in androgen-dependent and androgen-insensitive prostate cancer cells and found that LPA1 gene is differentially expressed in androgen-insensitive and LPA-responsive but not androgen-dependent and LPA-resistant cells. In human prostate specimens, expression of LPA1 gene was significantly higher in the cancer compared with the benign tissues. The androgen-dependent LNCaP cells do not express LPA1 and do not proliferate in response to LPA stimulation, implying LPA1 transduces cell growth signals. Accordingly, stable expression of LPA1 in LNCaP cells rendered them responsive to LPA-induced cell proliferation and decreased their doubling time in serum. Implantation of LNCaP-LPA1 cells resulted in increased rate of tumor growth in animals compared with those tumors that developed from the wild-type cells. Growth of LNCaP cells depends on androgen receptor activation, and we show that LPA1 transduces Gαi-dependent signals to promote nuclear localization of androgen receptor and cell proliferation. In addition, treatment with bicalutamide inhibited LPA-induced cell cycle progression and proliferation of LNCaP-LPA1 cells. These results suggest the possible utility of LPA1 as a drug target to interfere with progression of prostate cancer.

scholarly journals Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells

2014 ◽  
Vol 5 (11) ◽  
pp. 2922-2930 ◽  
Author(s):  
Claudia Sánchez-González ◽  
Carlos J. Ciudad ◽  
Véronique Noé ◽  
Maria Izquierdo-Pulido
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Prostate Cancer Cells ◽  
Down Regulation

Urolithins attenuate the function of the AR by repressing its expression, causing a down-regulation of PSA levels and inducing apoptosis. Our results suggest that a diet rich in ellagitannins could contribute to the prevention of prostate cancer.

scholarly journals DNA licensing as a novel androgen receptor mediated therapeutic target for prostate cancer

2009 ◽  
Vol 16 (2) ◽  
pp. 325-332 ◽  
Author(s):  
Jason M D'Antonio ◽  
Donald J Vander Griend ◽  
John T Isaacs
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Dna Replication ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Prostate Cancer Cells ◽  
Normal Prostate ◽  
Malignant Prostate

During middle G1 of the cell cycle origins of replication orchestrate the ordered assembly of the pre-replication complex (pre-RC), allowing licensing of DNA required for DNA replication. Cyclin-dependent kinase activation of the pre-RC facilitates the recruitment of additional signaling factors, which triggers DNA unwinding and replication, while limiting such DNA replication to once and only once per cell cycle. For both the normal and malignant prostate, androgen is the major stimulator of cell proliferation and thus DNA replication. In both cases, the binding of androgen to the androgen receptor (AR) is required. However, the biochemical cascade involved in such AR-stimulated cell proliferation and DNA synthesis is dramatically different in normal versus malignant prostate cells. In normal prostate, AR-stimulated stromal cell paracrine secretion of andromedins stimulates DNA replication within prostatic epithelial cells, in which AR functions as a tumor suppressor gene by inducing proliferative quiescence and terminal differentiation. By direct contrast, nuclear AR in prostate cancer cells autonomously stimulates continuous growth via incorporation of AR into the pre-RC. Such a gain of function by AR-expressing prostate cancer cells requires that AR be efficiently degraded during mitosis since lack of such degradation leads to re-licensing problems, resulting in S-phase arrest during the subsequent cell cycle. Thus, acquisition of AR as part of the licensing complex for DNA replication represents a paradigm shift in how we view the role of AR in prostate cancer biology, and introduces a novel vulnerability in AR-expressing prostate cancer cells apt for therapeutic intervention.

Casein kinase 2 inhibition attenuates androgen receptor function and cell proliferation in prostate cancer cells

The Prostate ◽  
2012 ◽  
Vol 72 (13) ◽  
pp. 1423-1430 ◽  
Author(s):  
Kai Yao ◽  
Hyewon Youn ◽  
Xiaoyan Gao ◽  
Bijun Huang ◽  
Fangjian Zhou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Casein Kinase ◽  
Casein Kinase 2 ◽  
Receptor Function ◽  
Prostate Cancer Cells ◽  
Androgen Receptor Function

scholarly journals Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells

2013 ◽  
Vol 20 (3) ◽  
pp. 431-441 ◽  
Author(s):  
Eiji Kashiwagi ◽  
Masaki Shiota ◽  
Akira Yokomizo ◽  
Momoe Itsumi ◽  
Junichi Inokuchi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Human Prostate ◽  
Receptor Subtype ◽  
Prostate Cancer Cells ◽  
Prostaglandin Receptor ◽  
Prostate Carcinogenesis ◽  
Castration Resistant

Although numerous epidemiological studies show aspirin to reduce risk of prostate cancer, the mechanism of this effect is unclear. Here, we first confirmed that aspirin downregulated androgen receptor (AR) and prostate-specific antigen in prostate cancer cells. We also found that aspirin upregulated prostaglandin receptor subtype EP3 but not EP2 or EP4. The EP3 antagonist L798106 and EP3 knockdown increased AR expression and cell proliferation, whereas the EP3 agonist sulprostone decreased them, indicating that EP3 affects AR expression. Additionally,EP3(PTGER3) transcript levels were significantly decreased in human prostate cancer tissues compared with those in normal human prostate tissues, suggesting that EP3 is important to prostate carcinogenesis. Decreased EP3 expression was also seen in castration-resistant subtype CxR cells compared with parental LNCaP cells. Finally, we found that aspirin and EP3 modulators affected prostate cancer cell growth. Taken together, aspirin suppressed LNCaP cell proliferation via EP3 signaling activation; EP3 downregulation contributed to prostate carcinogenesis and to progression from androgen-dependent prostate cancer to castration-resistant prostate cancer by regulating AR expression. In conclusion, cyclooxygenases and EP3 may represent attractive therapeutic molecular targets in androgen-dependent prostate cancer.

scholarly journals RANBP10 promotes glioblastoma progression by regulating the FBXW7/c-Myc pathway

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Jianbing Hou ◽  
Yudong Liu ◽  
Pan Huang ◽  
Yutao Wang ◽  
Dakun Pei ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Promoter Activity ◽  
Biological Function ◽  
Prostate Cancer Cells ◽  
Poor Survival ◽  
Evolutionarily Conserved

AbstractRAN binding protein 10 (RANBP10), a ubiquitously expressed and evolutionarily conserved protein, as a RAN-GTP exchange factor (GEF) to regulate several factors involved in cellular progression. Previous studies showed that RANBP10 was overexpressed in prostate cancer cells and was responsible for androgen receptor (AR) activation. However, the biological function of RANBP10 in glioblastoma (GBM) has not been studied. Here, we found that RANBP10 was overexpressed in GBM, and high RANBP10 expression was closely linked to poor survival of patients with GBM. Downregulation of RANBP10 significantly inhibited cell proliferation, migration, invasion, and tumor growth of GBM cells. In addition, we revealed that RANBP10 could suppress the promoter activity of FBXW7, and thereby increase the protein stability of c-Myc in GBM cells. Silencing of FBXW7 in RANBP10-knockdown GBM cells could partly negate the effects induced by RANBP10 downregulation. Taken together, our findings established that RANBP10 significantly promoted GBM progression by control of the FBXW7–c-Myc axis, and suggest that RANBP10 may be a potential target in GBM.

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