scholarly journals Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells

2021 ◽  
Author(s):  
Aashika Sekar ◽  
Aaron Leiblich ◽  
Josephine E.E.U Hellberg ◽  
Dhruv Sarma ◽  
Claudia C Mendes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Growth Regulation ◽  
Early Stage ◽  
Tumour Progression ◽  
Ecdysone Receptor ◽  
Cell Cycle Regulators ◽  
Castration Resistant Prostate Cancer ◽  
Steroid Dependent ◽  
Independent Form

Dysregulation of cell cycle components results in the development and progression of several cancer types. Unusually, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 have been linked to late-stage tumour progression in prostate cancer, rather than early-stage events. This change is associated with an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that binucleate secondary cells (SCs) of the Drosophila melanogaster male accessory gland (AG) share several functional and signalling similarities with human prostate epithelial cells. Upon mating, SC growth regulation switches from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control that induces genome endoreplication. Here, we demonstrate that the Drosophila Rb homologue, Rbf, and E2F1, as well as cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key mediators of SC growth and endoreplication both in virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and associated growth in SCs after mating, mirroring changes in CRPC. We also demonstrate that excess Rbf activity reversibly suppresses binucleation in adult SCs. Overall, our work reveals mechanistic parallels between the physiological switch to hormone-independent EcR signalling in SCs, and the pathological switch seen in CRPC, and suggests that the latter may represent the dysregulation of a currently unidentified physiological process, which permits AR signalling when androgen levels are low.

scholarly journals Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3975
Author(s):  
Marco A. De Velasco ◽  
Yurie Kura ◽  
Naomi Ando ◽  
Noriko Sako ◽  
Eri Banno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Late Stage ◽  
Early Stage ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Molecular Features ◽  
Context Specific

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

Androgen receptors in prostate cancer.

2002 ◽  
pp. 155-170 ◽  
Author(s):  
Z Culig ◽  
H Klocker ◽  
G Bartsch ◽  
A Hobisch
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Clinical Situation ◽  
Activation Function ◽  
Flufenamic Acid ◽  
Cell Cycle Regulators ◽  
Industrialized Countries ◽  
Chemopreventive Agents

The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.

scholarly journals Genetic Association Analysis of Cell Cycle Regulators Reveals YWHAZ Has Prognostic Significance in Prostate Cancer

2020 ◽  
Vol 17 (2) ◽  
pp. 209-216 ◽  
Author(s):  
CHIA-CHENG YU ◽  
LIH-CHYANG CHEN ◽  
WEN-HSIN LIN ◽  
VICTOR C. LIN ◽  
CHAO-YUAN HUANG ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Genetic Association ◽  
Association Analysis ◽  
Prognostic Significance ◽  
Cell Cycle Regulators ◽  
Genetic Association Analysis

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

Peptide vaccines with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive castration resistant prostate cancer: A randomized phase II study.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 3-3
Author(s):  
Hirotsugu Uemura ◽  
Takahiro Kimura ◽  
Takafumi Minami ◽  
Kazuhiro Yoshimura ◽  
Masahiro Nozawa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Low Dose ◽  
Early Stage ◽  
Phase 1 ◽  
Peptide Vaccine ◽  
Progression Free Survival ◽  
Peptide Vaccines ◽  
Castration Resistant Prostate Cancer ◽  
Peptide Vaccination ◽  
Castration Resistant

3 Background: We previously developed MHC class I restricted peptide vaccines for prostate cancer and carried out a phase 1 trial for castration resistant prostate cancer (CRPC) patients to assess safety and immunological evaluation. In the present study, we conducted a randomized phase 2 trial to evaluate the efficacy of peptide vaccination therapy for chemotherapy-naive CRPC patients. Methods: Early-stage CRPC (PSA<10ng/ml) patients positive for HLA-A02 or A24 or A3 super family were randomized into two treatment groups; peptide vaccine with low dose (1mg/day) dexamethasone (Dx) versus low dose Dx alone. Patients were vaccinated subcutaneously with 3 mg of selected peptides (max. 4 kinds) 6 times at two weeks interval. Dx 1mg/day p.o. was started on the first day of peptide vaccination. Toxicity was assessed monthly, and immunological responses such as cytotoxic T lymphocyte activity and clinical responses were evaluated every 3 months. The primary endpoint of this study is progression-free survival including serum PSA. Secondary endpoints are overall survival and safety. Results: A total of 83 chemotherapy-naive CRPC patients were selected for this trial. Of these 10 patients were excluded due to HLA type mismatch and exclusion criteria. 73 patients were enrolled and randomized; 37 in the vaccine treatment group and 36 in the Dx group. One patient in the Dx group self-withdrew from the study immediate after the randomization. Median time to PSA failure in the vaccine group was significant longer than the Dx group; 602 days vs 210 days, p<0.001 (Table). Conclusions: These findings suggest that combination therapy of peptide vaccines and low dose dexamethasone may be a promising tool for chemotherapy-naive CRPC patients. Clinical trial information: UMIN000000959.[Table: see text]

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.

Targeting the p300/CBP interactome through blockage of the CH1-domain triggers tumor regression in AR-positive and AR-negative xenograft models of castration-resistant prostate cancer (CRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3105-3105
Author(s):  
Valentino Cattori ◽  
Bernd Hentsch ◽  
Ulrich Kessler
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Small Molecule ◽  
Advanced Prostate Cancer ◽  
Tumor Regression ◽  
Clinical Investigation ◽  
Specific Antigen ◽  
Luciferase Reporter ◽  
Castration Resistant Prostate Cancer ◽  
Xenograft Models

3105 Background: In advanced prostate cancer, the paralog transcription co-activators p300/CBP are often highly expressed and have been associated with disease progression and poor prognosis. While several inhibitors of the bromo- and histone acetyltransferase domains of p300/CBP have been described, past efforts to develop drug-like ligands of other regions of this attractive target have been unsuccessful. Methods: A rationally designed small molecule modulator of the CH1-domain of p300/CBP was tested in a panel of prostate cancer cell lines, followed by cell cycle analysis and beta-galactosidase staining. Inhibition of the p300-dependent androgen receptor (AR) related transcriptional response was determined in a luciferase reporter assay and by qPCR analysis of expression of downstream genes like prostate-specific antigen (PSA), transmembrane protease-serine 2 (TMPRSS2) and prostein (SLC45A3). In vivo effects were evaluated in cell line- and patient-derived xenograft models of CRPC. Results: Selective blockage of the CH1 domain of p300/CBP results in sustainable anti-proliferative effects in AR-positive and AR-negative prostate cancer cells inducing apoptosis and/or senescence. Transcriptome and gene expression analyses revealed the downregulation of various drivers of cell cycle progression as well as decreased expression of hormone-induced, AR-regulated genes. In enzalutamide-resistant xenograft models of CRPC, oral administration of the compound triggered tumor regression/eradication at well tolerated doses. Serum PSA levels were strongly decreased in treated animals. Conclusions: Simultaneous inhibition of both, AR-signaling and downregulation of p300/CBP activity, may cause profound and long lasting antitumoral effects in patients with advanced prostate cancer. Future clinical investigation of this novel oral small molecule agent is warranted.

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