scholarly journals Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing

2019 ◽  
Author(s):  
Kalpit Shah ◽  
Teresa Gagliano ◽  
Lisa Garland ◽  
Timothy O’Hanlon ◽  
Daria Bortolotti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Therapeutic Interventions ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen-deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line anti-androgen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on anti-androgen therapies is only 8 to 19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR-signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation- and inhibition-of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D-invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist driven tumor invasion. In conclusion, until now, AR signaling has been primarily thought to modulate transcriptome of prostate epithelial cells by inducing or suppressing gene expression. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

scholarly journals Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

Oncogene ◽  
2020 ◽  
Vol 39 (39) ◽  
pp. 6172-6189
Author(s):  
Kalpit Shah ◽  
Teresa Gagliano ◽  
Lisa Garland ◽  
Timothy O’Hanlon ◽  
Daria Bortolotti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Therapeutic Interventions ◽  
Prostate Cancer Cells

Abstract Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8–19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation and inhibition of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist-mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist-driven tumor invasion. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

Abstract 2083: Alternative splicing regulation by the androgen receptor in prostate cancer cells

2020 ◽  
Author(s):  
Lucas Germain ◽  
Camille Lafront ◽  
Jolyane Beaudette ◽  
Raghavendra Tejo Karthik Poluri ◽  
Cindy Weidmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Splicing Regulation ◽  
Prostate Cancer Cells

Androgen-dependent regulation of Her-2/neu in prostate cancer cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10099-10099
Author(s):  
R. Berger ◽  
D. I. Lin ◽  
M. Nieto ◽  
S. Signoretti ◽  
W. C. Hahn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Prostate Cancer Cells ◽  
In Vivo Experiments ◽  
Her 2

10099 Background: The mechanisms underlying the progression of prostate cancer to androgen independence remain poorly understood. Overexpression of Her-2/neu (c-ErbB2) activates the androgen receptor pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. Methods: Androgen-sensitive prostate cancer cell line LNCaP was used as a model system in vitro and in vivo. Experiments in mice were undertaken by injecting cells orthotopically into the ventral lobe of the mice prostate. Results: Here, we report that androgen receptor (AR) and Her-2/neu reciprocally regulate each other in LNCaP human prostate cancer cells. Absence of androgens, AR blockade with Casodex (bicalutamide) or suppression of AR with RNAi induced Her-2/neu protein expression and phosphorylation in vitro and in vivo. Similarly, suppression of Her-2-neu expression resulted in AR upregulation. In contrast, upon re-administration of androgens, Her-2/neu mRNA, protein and phosphorylation levels decreased linearly with increasing concentrations of androgens as LNCaP cells re-entered the cell cycle. Conclusions: Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting androgen-independent survival of prostate cancer cells. No significant financial relationships to disclose.

scholarly journals The role of STEAP2 in aggressive prostate cancer traits and androgen response

2021 ◽  
Author(s):  
◽  
Leia A. Jones
Keyword(s):  
Prostate Cancer ◽  
Monoclonal Antibody ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Migration And Invasion ◽  
Prostate Cancer Cells ◽  
Aggressive Prostate Cancer

The prognosis of localised prostate cancer is generally promising, as many tumours remain dormant and therefore do not require immediate intervention. In contrast, once metastasised, the prognosis for aggressive prostate cancer is often poor, highlighting the need for novel, effective treatment approaches. The expression of the six transmembrane epithelial antigen of the prostate2 (STEAP2) cell surface protein is increased in aggressive prostate cancer compared to normal prostate tissue. In vitro studies have shown STEAP2 to aid in prostate cancer progression, and as such this molecule shows promise as a potential novel therapeutic target in the treatment of advanced disease. The aim of this thesis was to develop a comprehensive understanding of the mechanistic role of STEAP2 in promoting aggressive prostate cancer traits and evaluate if its knock-out has the capacity to reduce the invasive potential of prostate cancer cells in vitro. As prostate cancer is a largely androgen dependent disease, this thesis also aimed to evaluate the effects of STEAP2 inhibition on the expression of the androgen receptor and androgen-regulated genes. This study developed and optimised a protocol for generating a set of 3D prostate cancer spheroids to provide more representative models of the in vivo prostate cancer environment. In this thesis, one commercial anti-STEAP2 polyclonal antibody and a panel of anti-STEAP2 monoclonal antibodies were selected for proof-of-concept studies where their effects on reducing prostate cancer cell viability were assessed. Receptor internalisation of STEAP2 was evaluated upon anti-STEAP2 monoclonal antibody binding to determine its suitability for use with antibody-drug conjugate technology. STEAP2 expression was knocked out using CRISPR/Cas9 genome engineering technology in two prostate cancer cell lines to evaluate its impact on cell proliferation, migration and invasion. Furthermore, gene expression profiling was conducted to explore interactions between STEAP2, the androgen receptor and a panel of androgen-regulated genes (PSA, FKBP5, GPRC6A and TMPRSS2) following: 1) anti-STEAP2 antibody treatment, 2) STEAP2-knockout and 3) the growth of prostate cancer cells in androgen-depleted conditions. The data presented in this thesis demonstrate that inhibition of STEAP2 by both the polyclonal anti-STEAP2 antibody and lead anti-STEAP2 monoclonal antibody significantly reduced prostate cancer cell viability. STEAP2 receptor internalisation was triggered following treatment of prostate cancer cells with the anti-STEAP2 monoclonal antibody, demonstrating its potential utility with antibody-drug conjugate technology in the future. STEAP2 knockout prostate cancer cells exhibited decreased cell proliferation, migration and invasion in comparison to wild-type cells. These promising findings highlight the therapeutic value of STEAP2-knockout in inhibiting invasive tumour cell traits. Gene expression data from both STEAP2-knockout cells and androgen-depleted cells suggest that STEAP2 may be involved in crosstalk between the androgen receptor and androgen-regulated genes. STEAP2 could therefore provide a novel target in conjunction with current conventional androgen deprivation therapy. In conclusion, the in vitro findings presented herein suggest STEAP2 as a viable target for the development of more tailored and personalised therapeutic agents to improve the clinical management of men with aggressive prostate cancer.

scholarly journals The Natural Compound Myricetin Effectively Represses the Malignant Progression of Prostate Cancer by Inhibiting PIM1 and Disrupting the PIM1/CXCR4 Interaction

2018 ◽  
Vol 48 (3) ◽  
pp. 1230-1244 ◽  
Author(s):  
Chen Ye ◽  
Chao Zhang ◽  
Hai Huang ◽  
Bo Yang ◽  
Guangan Xiao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Integration Site ◽  
Leukemia Virus ◽  
In Vivo Studies ◽  
Prostate Cancer Cells ◽  
Clinicopathologic Characteristics

Background/Aims: Natural compounds are a promising resource for anti-tumor drugs. Myricetin, an abundant flavonoid found in the bark and leaves of bayberry, shows multiple promising anti-tumor functions in various cancers. Methods: The cytotoxic, pro-apoptotic, and anti-metastatic effects of myricetin on prostate cancer cells were investigated in both in vitro and in vivo studies. Short-hairpin RNA knockdown of the proviral integration site for Moloney murine leukemia virus-1 (PIM1), pull-down and co-immunoprecipitation assays, and an intracellular Ca2+ flux assay were used to investigate the potential underlying mechanism of myricetin. ONCOMINE database data mining and immunohistochemical analysis of prostate cancer tissues were used to evaluate the expression of PIM1 and CXCR4, as well as the correlation between PIM1 and CXCR4 expression and the clinicopathologic characteristics and prognoses of prostate cancer patients. Results: Myricetin exerted selective cytotoxic, pro-apoptotic, and anti-metastatic effects on prostate cancer cells by inhibiting PIM1 and disrupting the PIM1/CXCR4 interaction. Moreover, PIM1 and CXCR4 were coexpressed and associated with aggressive clinicopathologic traits and poor prognosis in prostate cancer patients. Conclusion: These results offer preclinical evidence for myricetin as a potential chemopreventive and therapeutic agent for precision medicine tailored to prostate cancer patients characterized by concomitant elevated expression of PIM1 and CXCR4.

Alternative splicing regulation by the androgen receptor in prostate cancer cells

2020 ◽  
Vol 202 ◽  
pp. 105710 ◽  
Author(s):  
Lucas Germain ◽  
Camille Lafront ◽  
Jolyane Beaudette ◽  
Raghavendra Tejo Karthik Poluri ◽  
Cindy Weidmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Splicing Regulation ◽  
Prostate Cancer Cells

scholarly journals Interleukin-10 Induces Expression of Neuroendocrine Markers and PDL1 in Prostate Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Abrar Samiea ◽  
Jeff S. J. Yoon ◽  
Christopher J. Ong ◽  
Amina Zoubeidi ◽  
Thomas C. Chamberlain ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Immune Cells ◽  
Prostate Cancer Cell ◽  
Elevated Serum ◽  
Interleukin 10 ◽  
Prostate Cancer Cells

Interleukin-10 (IL10) is best studied for its inhibitory action on immune cells and ability to suppress an antitumour immune response. But IL10 also exerts direct effects on nonimmune cells such as prostate cancer epithelial cells. Elevated serum levels of IL10 observed in prostate and other cancer patients are associated with poor prognosis. After first-line androgen-deprivation therapy, prostate cancer patients are treated with androgen receptor antagonists such as enzalutamide to inhibit androgen-dependent prostate cancer cell growth. However, development of resistance inevitably occurs and this is associated with tumour differentiation to more aggressive forms such as a neuroendocrine phenotype characterized by expression of neuron specific enolase and synaptophysin. We found that treatment of prostate cancer cell lines in vitro with IL10 or enzalutamide induced markers of neuroendocrine differentiation and inhibited androgen receptor reporter activity. Both also upregulated the levels of PDL1, which could promote tumour survival in vivo through its interaction with the immune cell inhibitory receptor PD1 to suppress antitumour immunity. These findings suggest that IL10’s direct action on prostate cancer cells could contribute to prostate cancer progression independent of IL10’s suppression of host immune cells.

Inhibition of alternative splicing using the spliceosome inhibitor Pladienolide B reduces aggressiveness of prostate cancer cells in vitro

2018 ◽  
Author(s):  
Juan M Jimenez-Vacas ◽  
Vicente Herrero-Aguayo ◽  
Antonio J Leon-Gonzalez ◽  
Gomez-Gomez Enrique ◽  
Prudencio Saez-Martinez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Pladienolide B
Sign in / Sign up

Export Citation Format

Share Document