scholarly journals HES6 drives a critical AR transcriptional programme to induce castration‐resistant prostate cancer through activation of an E 2 F 1‐mediated cell cycle network

2014 ◽  
Vol 6 (5) ◽  
pp. 651-661 ◽  
Author(s):  
Antonio Ramos‐Montoya ◽  
Alastair D Lamb ◽  
Roslin Russell ◽  
Thomas Carroll ◽  
Sarah Jurmeister ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Studies of a novel modified E2F-targeted peptide with activity against castration-resistant prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 205-205
Author(s):  
Joseph R. Bertino ◽  
Zoltan Szekely ◽  
Kathleen W Scotto
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Replication Proteins ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Stability

205 Background: The E2F family of genes encodes transcription factors that are key to the regulation of a number of target genes, including those encoding cyclins , CDKs , checkpoints regulators, and DNA repair and replication proteins. One of the primary functions of the E2Fs is to control the cell cycle, playing a major role in regulating the G1/S transition. One of the primary regulators of E2F expression is the retinoblastoma gene, RB, a chromatin associated protein that, in its unphosphorylated state, binds to and negatively regulates E2F; hyperphosphorylation of RB releases E2F, allowing cell cycle progression. Many tumor cells have mutant or dysfunctional RB, allowing the aberrant overexpression of the E2Fs and tumor cell proliferation; this aberrant overexpression is better tolerated when p53 is mutated, suppressing subsequent apoptosis. Overexpression of E2F, particularly E2F1, has thus been an attractive target for therapeutic intervention. However, this approach has not yet been successful, most likely due to the redundancy of the E2Fs and the lack of biomarkers for sensitivity. Methods: Using phage display, we have previously identified a novel peptide that, when coupled with penetratin (PEP) to enhance uptake), targets the E2F consensus site in E2F1,2 and 3a, leading to the downregulation of the activating E2Fs and their downstream targets. We have recently enhanced the stability and potency of this peptide by substituting L-Arg within the peptide with D-Arg. Results: Castrate resistant prostate cancer (CRPC) cells, DU-145, lack functional RB, have mutant p53, and are more sensitive to the D-Arg PEP than LnCap or PC-3 cells, with functional RB. Xenograft studies in mice show that the PEP, when encapsulated in PEGylated liposomes (PL-D-Arg PEP) , regresses DU-145 tumors without toxicity. Current studies are examining the combination of the (PL-D-Arg PEP) with taxotere, cisplatin and irradiation in prostate cancer xenografts and organoids from patients. Conclusions: A peptide that inhibits transcription of the activating E2Fs has promise to treat CRPC.

TACC2 Is an Androgen-Responsive Cell Cycle Regulator Promoting Androgen-Mediated and Castration-Resistant Growth of Prostate Cancer

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Survival Rates ◽  
Tumor Formation ◽  
Castration Resistant Prostate Cancer ◽  
Cellular Models ◽  
Castration Resistant ◽  
Hormone Refractory ◽  
Immunocompromised Mice

Despite the existence of effective antiandrogen therapy for prostate cancer, the disease oftenprogresses to castration-resistant states. Elucidation of the molecular mechanisms underlying theresistance for androgen deprivation in terms of the androgen receptor (AR)-regulated pathwaysis a requisite to manage castration-resistant prostate cancer (CRPC). Using a ChIP-cloning strategy,we identified functional AR binding sites (ARBS) in the genome of prostate cancer cells. Wediscovered that a centrosome- and microtubule-interacting gene, transforming acidic coiled-coilprotein 2 (TACC2), is a novel androgen-regulated gene.Weidentified a functional AR-binding site(ARBS) including two canonical androgen response elements in the vicinity of TACC2 gene, inwhich activated hallmarks of histone modification were observed. Androgen-dependent TACC2induction is regulated by AR, as confirmed by AR knockdown or its pharmacological inhibitorbicalutamide. Using long-term androgen-deprived cells as cellular models of CRPC, we demonstratedthat TACC2 is highly expressed and contributes to hormone-refractory proliferation, assmall interfering RNA-mediated knockdown of TACC2 reduced cell growth and cell cycle progression.By contrast, in TACC2-overexpressing cells, an acceleration of the cell cycle was observed. Invivo tumor formation study of prostate cancer in castrated immunocompromised mice revealedthat TACC2 is a tumor-promoting factor. Notably, the clinical significance of TACC2 was demonstratedby a correlation between high TACC2 expression and poor survival rates. Taken togetherwith the critical roles of TACC2 in the cell cycle and the biology of prostate cancer, we infer thatthe molecule is a potential therapeutic target in CRPC

scholarly journals Genomic Resistance Patterns to Second-Generation Androgen Blockade in Paired Tumor Biopsies of Metastatic Castration-Resistant Prostate Cancer

2017 ◽  
pp. 1-11 ◽  
Author(s):  
G. Celine Han ◽  
Justin Hwang ◽  
Stephanie A.M. Wankowicz ◽  
Zhenwei Zhang ◽  
David Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Androgen Deprivation Therapy ◽  
Second Generation ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Androgen Deprivation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Line Of Therapy

Purpose Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy. Patients and Methods We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgen-deprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor. Results We observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A ( CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade—palbociclib and ribociclib. Conclusion CDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamide-resistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.

scholarly journals The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer: The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2929
Author(s):  
Yi-Hua Sheng ◽  
Wohn-Jenn Leu ◽  
Ching-Nung Chen ◽  
Jui-Ling Hsu ◽  
Ying-Tung Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Mitochondrial Dysfunction ◽  
Anticancer Activity ◽  
Intracellular Signaling ◽  
G1 Phase ◽  
G1 Arrest ◽  
Ros Production ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Because conventional chemotherapy is not sufficiently effective against prostate cancer, various examinations have been performed to identify anticancer activity of naturally occurring components and their mechanisms of action. The (+)-brevipolide H, an α-pyrone-based natural compound, induced potent and long-term anticancer effects in human castration-resistant prostate cancer (CRPC) PC-3 cells. Flow cytofluorometric analysis with propidium iodide staining showed (+)-brevipolide H-induced G1 arrest of cell cycle and subsequent apoptosis through induction of caspase cascades. Since Akt/mTOR pathway has been well substantiated in participating in cell cycle progression in G1 phase, its signaling and downstream regulators were examined. Consequently, (+)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K. The c-Myc inhibition and downregulation of G1 phase cyclins were also attributed to (+)-brevipolide H action. Overexpression of myristoylated Akt significantly rescued mTOR/p70S6K and downstream signaling under (+)-brevipolide H treatment. ROS and Ca2+, two key mediators in regulating intracellular signaling, were determined, showing that (+)-brevipolide H interactively induced ROS production and an increase of intracellular Ca2+ levels. The (+)-Brevipolide H also induced the downregulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and loss of mitochondrial membrane potential, indicating the contribution of mitochondrial dysfunction to apoptosis. In conclusion, the data suggest that (+)-brevipolide H displays anticancer activity through crosstalk between ROS production and intracellular Ca2+ mobilization. In addition, suppression of Akt/mTOR/p70S6K pathway associated with downregulation of G1 phase cyclins contributes to (+)-brevipolide H-mediated anticancer activity, which ultimately causes mitochondrial dysfunction and cell apoptosis. The data also support the biological significance and, possibly, clinically important development of natural product-based anticancer approaches.

scholarly journals Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

2018 ◽  
Vol 47 (2) ◽  
pp. 759-773 ◽  
Author(s):  
SongTao Xiang ◽  
PeiLiang Zou ◽  
JingJing Wu ◽  
Fang Zheng ◽  
Qing Tang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Protein Expression ◽  
Cell Cycle Distribution ◽  
Muc1 Expression ◽  
Castration Resistant Prostate Cancer ◽  
Antitumor Effects ◽  
Castration Resistant ◽  
Muc1 Gene

Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.

scholarly journals MicroRNA-23b and microRNA-27b plus flutamide treatment enhances apoptosis rate and decreases CCNG1 expression in a castration-resistant prostate cancer cell line

Tumor Biology ◽  
2018 ◽  
Vol 40 (11) ◽  
pp. 101042831880301 ◽  
Author(s):  
Ruan CA Pimenta ◽  
Nayara I Viana ◽  
Gabriela Q Amaral ◽  
Rubens Park ◽  
Denis R Morais ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Line ◽  
Target Gene ◽  
Prostate Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Number Of Cells

The acquisition of a castration-resistant prostate cancer phenotype by prostate cancer cells is the alteration that has the worst prognosis for patients. The aim of this study was to evaluate the role of the microRNAs-23b/-27b as well as the possible CCNG1 target gene in tissue samples from patients with localized prostate cancer that progressed to castration-resistant prostate cancer and in a castration-resistant prostate cancer cell line (PC-3). The microRNAs and target gene expression levels of the surgical specimens were analyzed by quantitative real-time polymerase chain reaction. The prostate cancer cell line, PC-3, was transfected with pre-miR-23b, pre-miR-27b, and their respective controls using Lipofectamine RNAiMAX and exposed or not to flutamide. After transfections, expression levels of both the microRNAs and the gene, CCNG1, were analyzed by quantitative real-time polymerase chain reaction. The apoptosis and cell cycle assays were performed on the mini MUSE cytometer. MicroRNAs-23b/-27b were underexpressed in surgical specimens of prostate cancer; however, their target gene, CCNG1, was overexpressed in 69% of the cases. After transfection with the microRNAs-23b/-27b and flutamide, we observed a reduction in gene expression compared with cells that were treated only with microRNAs or only with flutamide. In the apoptosis assay, we demonstrated cell sensitization following transfection with microRNAs-23b/-27b and potentiation when co-administered with flutamide. The number of cells in apoptosis was almost three times higher with the simultaneous treatments (miR + flutamide) compared with the control (p < 0.05). In the cell cycle assay, only flutamide treatment showed better results; a higher number of cells were found in the G0-G1 phase, and a lower percentage of cells completed the final phase of the cycle (p < 0.05). We conclude that microRNAs-23b/-27b are downexpressed in prostate cancer, and their target gene, CCNG1, is overexpressed. We postulated that microRNAs-23b/-27b sensitize the PC-3 cell line and that after the addition of flutamide in the apoptosis assay, we would observe synergism in the treatments between miR and flutamide. In the cell cycle assay, the use of flutamide was sufficient to decrease the number of cells in mitosis. Therefore, we postulate that microRNAs, along with other drugs, may become very useful therapeutic tools in the treatment of castration-resistant prostate cancer.

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