The emerging role of noncoding RNA in prostate cancer progression and its implication on diagnosis and treatment

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Castration Resistant Prostate Cancer ◽  
Systematic Analysis ◽  
Castration Resistant ◽  
Insight Into ◽  
Generation Sequencing

Recent transcriptome studies using next-generation sequencing have detected aberrant changes in the expression of noncodingRNAs (ncRNAs) associated with cancer. For prostate cancer, the expression levels of ncRNAs including microRNAsand long noncoding RNAs are strongly associated with diagnosis, carcinogenesis and tumor growth. Moreover, androgenand its cognate receptor, androgen receptor (AR), regulate various signaling pathways for prostate tumor growth. In addition,progression to lethal castration-resistant prostate cancer (CRPC) is also owing to AR function. Systematic analysis ofAR-binding sites and their regulated transcripts revealed that many ncRNAs are widely regulated at the transcriptionallevel. Thus, recent studies provide new insight into the complicated molecular mechanism of prostate cancer progression.This review focused on the role of various ncRNAs in prostate cancer and the association between their expression andCRPC.

scholarly journals Therapeutic Targeting of Histone Lysine Demethylase KDM4B Blocks the Growth of Castration-Resistant Prostate Cancer

2021 ◽  
Author(s):  
Lingling Duan ◽  
Yu-An Chen ◽  
Yanping Liang ◽  
Zhenhua Chen ◽  
Jun Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Epigenetic Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Lncap Cells ◽  
Castration Resistant ◽  
Histone Lysine ◽  
Histone Lysine Demethylase ◽  
Lysine Demethylase

Abstract Background: Accumulating evidence points to epigenetic mechanisms as essential in tumorigenesis. Treatment that targets epigenetic regulators is becoming an attractive strategy for cancer therapy. The role of epigenetic therapy in prostate cancer (PCa) remains elusive. Previously we demonstrated a correlation of levels of histone lysine demethylase KDM4B with the appearance of castration resistant prostate cancer (CRPC) and identified a small molecular inhibitor of KDM4B, B3. In this study, we aim to define the role of KDM4B in promoting PCa progression and test the efficacy of B3 using clinically relevant PCa models. Methods: KDM4B was overexpressed in LNCaP cells or knocked down (KD) in 22Rv1 cells. The specificity of B3 was determined in vitro using recombinant KDM proteins and in vivo using 22Rv1 cell lysates. The efficacy of B3 monotherapy or in combination with androgen receptor (AR) antagonist enzalutamide or the mTOR inhibitor rapamycin was tested using xenograft models in castrated mice. Comparative transcriptomic analysis was performed on KDM4B KD and B3-treated 22Rv1 cells to determine the on-target (KDM4B-dependent) and off-target (non-KDM4B-associated) effects of B3.Results: Overexpression of KDM4B in LNCaP cells enhanced its tumorigenicity whereas knockdown of KDM4B in 22Rv1 cells reduced tumor growth in castrated mice. B3 suppressed the growth of both 22Rv1 and VCaP xenografts and sensitized 22Rv1 cells to enzalutamide inhibition. B3 also inhibited 22Rv1 tumor growth synergistically with rapamycin that resulted in cell apoptosis. Mechanistically, B3 inhibited expression of AR-V7 and genes involved in epithelial-to-mesenchymal transition. DNA replication stress marker gH2A.X was upregulated by B3, which is further increased when combined with rapamycin. Based on transcriptomic and biochemical analyses, B3 inhibits both H3K9me3 and H3K27me3 demethylase activity, which is believed to underlie its anti-tumor action. Conclusions: Our studies establish KDM4B as a potent target for CRPC and B3 as a potential therapeutic agent. B3 as monotherapy or in combination with other anti-PCa therapeutics offers proof of principle for the clinical translation of epigenetic therapy targeting KDMSs for CRPC patients.

Blocking GRP/GRP-R Signaling Decreases Expression of Androgen Receptor Splice Variants and Inhibits Tumor Growth in Castration-resistant Prostate Cancer

2021 ◽  
Author(s):  
Thomas C Case ◽  
Alyssa Merkel ◽  
Marisol Ramirez-Solano ◽  
Qi Liu ◽  
Julie A Sterling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Fluorescent Protein ◽  
Splice Variants ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Reporter Vector

Abstract Background: Clinical management of castration-resistant prostate cancer (CRPC) resulting from androgen deprivation therapy (ADT) remains challenging. Previously, we have reported that long-term ADT increases the neuroendocrine (NE) hormone – Gastrin Releasing Peptide (GRP) and its receptor (GRP-R) expression in prostate cancer (PC) cells. Further, we demonstrated that activation of GRP/GRP-R signaling increases androgen receptor (AR) splice variants (ARVs) expression through activating NF-κB signaling thereby contributing cancer progression to CRPC. Most importantly, as a cell surface protein, GRP-R is easily targeted by drugs to block GRP/GRP-R signaling. Here, we aim to investigate if blocking GRP/GRP-R signaling by targeting GRP-R using GRP-R antagonist is sufficient to control CRPC progression, including in therapy-induced (t) neuroendocrine prostate cancer (tNEPC). Methods: Bone-growing NEPC cells were generated by treating androgen dependent LNCaP PC cells with anti-androgen (MDV3100) for more than 3 months. RC-3095, a selective GRP-R antagonist, was used for blocking GRP/GRP-R signaling. The NGL vector [a NF-kB responsive reporter vector which has Luciferase and Green Fluorescent Protein (GFP) reporter genes] was used to measure NF-kB activity and the ARR2PB-Luc vector (an AR responsive reporter vector) was used to measure AR activity in the PC cells. For in vivo experiments, the effect of RC-3095 on CRPC was observed in subcutaneous CRPC and bone-growing tNEPC tumor models.Results: Our studies show that blocking GRP/GRP-R signal by targeting GRP-R using RC-3095 efficiently inhibits NF-κB activity and ARVs (AR-V7) expression in CRPC and tNEPC cells. In addition, blocking of GRP/GRP-R signaling by targeting GRP-R can sensitize CRPC cells to anti-androgen treatment. Further, preclinical animal studies indicate combination of GRP-R antagonist (targeting ARVs) with anti-androgen [targeting full-length AR (AR-FL)] is sufficient to inhibit CRPC and tNEPC tumor growth.Conclusion: Our findings strongly indicate that blocking of GRP/GRP-R signaling in combination with ADT is a potential new approach to control CRPC tumor growth, including ADT induced tNEPC.

scholarly journals Therapeutic Targeting of Histone Lysine Demethylase KDM4B Blocks the Growth of Castration-resistant Prostate Cancer

2021 ◽  
Author(s):  
Lingling Duan ◽  
Yu-An Chen ◽  
Yanping Liang ◽  
Zhenhua Chen ◽  
Jun Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Epigenetic Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Lncap Cells ◽  
Castration Resistant ◽  
Histone Lysine ◽  
Histone Lysine Demethylase ◽  
Lysine Demethylase

Abstract Background: Accumulating evidence points to epigenetic mechanisms as essential in tumorigenesis. Treatment that targets epigenetic regulators is becoming an attractive strategy for cancer therapy. The role of epigenetic therapy in prostate cancer (PCa) remains elusive. Previously we demonstrated a correlation of levels of histone lysine demethylase KDM4B with the appearance of castration resistant prostate cancer (CRPC) and identified a small molecular inhibitor of KDM4B, B3. In this study, we aim to define the role of KDM4B in promoting PCa progression and test the efficacy of B3 using clinically relevant PCa models. Methods: KDM4B was overexpressed in LNCaP cells or knocked down (KD) in 22Rv1 cells. The specificity of B3 was determined in vitro using recombinant KDM proteins and in vivo using 22Rv1 cell lysates. The efficacy of B3 monotherapy or in combination with androgen receptor (AR) antagonist enzalutamide or the mTOR inhibitor rapamycin was tested using xenograft models in castrated mice. Comparative transcriptomic analysis was performed on KDM4B KD and B3-treated 22Rv1 cells to determine the on-target (KDM4B-dependent) and off-target (non-KDM4B-associated) effects of B3.Results: Overexpression of KDM4B in LNCaP cells enhanced its tumorigenicity whereas knockdown of KDM4B in 22Rv1 cells reduced tumor growth in castrated mice. B3 suppressed the growth of both 22Rv1 and VCaP xenografts and sensitized 22Rv1 cells to enzalutamide inhibition. B3 also inhibited 22Rv1 tumor growth synergistically with rapamycin that resulted in cell apoptosis. Mechanistically, B3 inhibited expression of AR-V7 and genes involved in epithelial-to-mesenchymal transition. DNA replication stress marker γH2A.X was upregulated by B3, which is further increased when combined with rapamycin. Based on transcriptomic and biochemical analyses, B3 inhibits both H3K9me3 and H3K27me3 demethylase activity, which is believed to underlie its anti-tumor action.Conclusions: Our studies establish KDM4B as a potent target for CRPC and B3 as a potential therapeutic agent. B3 as monotherapy or in combination with other anti-PCa therapeutics offers proof of principle for the clinical translation of epigenetic therapy targeting KDMSs for CRPC patients.

scholarly journals Correction to: The role of JMJD6/U2AF65/AR-V7 axis in castration-resistant prostate cancer progression

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dali Tong
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Prostate Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

An amendment to this paper has been published and can be accessed via the original article.

scholarly journals Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

2020 ◽  
Author(s):  
Chenchu Lin ◽  
Alicia M. Blessing ◽  
Thomas L. Pulliam ◽  
Yan Shi ◽  
Sandi R. Wilkenfeld ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Protein Kinase ◽  
Tumor Growth ◽  
Disease Progression ◽  
Mouse Models ◽  
Cancer Progression ◽  
Signaling Cascade ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

AbstractPrevious work has suggested androgen receptor (AR) signaling mediates cancer progression in part through the modulation of autophagy. Accordingly, we demonstrate that chloroquine, an inhibitor of autophagy, can inhibit tumor growth in preclinical mouse models of castration-resistant prostate cancer (CRPC). However, clinical trials testing chloroquine derivatives in men with CRPC have yet to yield promising results, potentially due to side effects. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular (inducible overexpression and shRNA-mediated knockdown), genetic (CRISPR/Cas9), and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2; a kinase with a restricted expression profile), 5’-AMP-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase 1 (ULK1). These findings are consistent with data indicating CAMKK2-AMPK-ULK1 signaling correlates with disease progression in genetic mouse models and patient tumor samples. Importantly, CAMKK2 disruption impaired tumor growth and prolonged survival in multiple CRPC preclinical mouse models. Finally, we demonstrate that, similar to CAMKK2 inhibition, a recently described inhibitor of AMPK-ULK1 signaling blocked autophagy, cell growth and colony formation in prostate cancer cells. Taken together, our findings converge to demonstrate that AR signaling can co-opt the CAMKK2-AMPK-ULK1 signaling cascade to promote prostate cancer by increasing autophagy. Further, we propose that an inhibitor of this signaling cascade could serve as an alternative, more specific therapeutic compared to existing inhibitors of autophagy that, to date, have demonstrated limited efficacy in clinical trials due to their toxicity and poor pharmacokinetics.

scholarly journals Role of Signaling Transduction Pathways in Development of Castration-Resistant Prostate Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Takahiro Inoue ◽  
Osamu Ogawa
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Castration Resistant Prostate Cancer ◽  
Novel Treatments ◽  
Resistant Disease ◽  
Castration Resistant ◽  
Almost All

Almost all patients who succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard treatment for this disease and is associated with modest prolongation of survival, there is an urgent need for novel treatments for castration-resistant prostate cancer (CRPC). Great advances in our understanding of the biological and molecular mechanisms of prostate cancer progression have resulted in many clinical trials of numerous targeted therapies. In this paper, we review mechanisms of CRPC development, with particular focus on recent advances in the understanding of specific intracellular signaling pathways participating in the proliferation of CRPC cells.

AR Copy Number and AR Signaling-directed Therapies in Castrationresistant Prostate Cancer

2018 ◽  
Vol 18 (9) ◽  
pp. 869-876
Author(s):  
Samanta Salvi ◽  
Vincenza Conteduca ◽  
Cristian Lolli ◽  
Sara Testoni ◽  
Valentina Casadio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number ◽  
Clinical Trial Design ◽  
Complete Information ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Cancer ◽  
Hormone Sensitive ◽  
Predictive And Prognostic Biomarker

Background: Adaptive upregulation of Androgen Receptor (AR) is the most common event involved in the progression from hormone sensitive to Castration-Resistant Prostate Cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. Objective: In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR Copy Number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Conclusion: Outcomes of CRPC patients are reported to be highly variable as the consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

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