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

PTEN-mediated G1 cell-cycle arrest in LNCaP prostate cancer cells is associated with altered expression of cell-cycle regulators

The Prostate ◽  
2009 ◽  
Vol 70 (2) ◽  
pp. 135-146 ◽  
Author(s):  
P.W. van Duijn ◽  
A.C.J. Ziel-van der Made ◽  
J.A.G. van der Korput ◽  
J. Trapman
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Cycle Regulators ◽  
Prostate Cancer Cells ◽  
Altered Expression ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

scholarly journals Genomic alterations impact cell cycle-related genes during prostate cancer progression

2021 ◽  
Author(s):  
Salma Ben-Salem ◽  
Varadha Balaji Venkadakrishnan ◽  
Hannelore V Heemers
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cancer Progression ◽  
Treatment Resistance ◽  
Cell Cycle Regulators ◽  
Genomic Alterations ◽  
M Phase ◽  
Genes Encoding ◽  
Treatment Naïve ◽  
Cycle Dependent

The recent genomic characterization of patient specimens has started to reveal the landscape of somatic alterations in clinical prostate cancer (CaP) and its association with disease progression and treatment resistance. The extent to which such alterations impact hallmarks of cancer is still unclear. Here, we interrogate genomic data from thousands of clinical CaP specimens that reflect progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP for alterations in cell cycle-associated and -regulated genes, which are central to cancer initiation and progression. We evaluate gene signatures previously curated to evaluate G1-S and G2-M phase transitions or to represent the cell cycle-dependent proteome. The resulting CaP (stage)-specific overview confirmed the presence of well-known driver alterations impacting for instance the genes encoding p53 and MYC, and uncovered novel previously unrecognized mutations that affect others such as the PKMYT1 and MTBP genes. The cancer dependency and drugability of representative genomically altered cell cycle determinants was verified also. Taken together, these analyses on hundreds of often less-characterized cell cycle regulators expand considerably the scope of genomic alterations associated with CaP cell proliferation and cell cycle, and isolate such regulatory proteins as putative drivers of CaP treatment resistance and entirely novel therapeutic targets for CaP therapy.

scholarly journals Novel insights in cell cycle dysregulation during prostate cancer progression

2021 ◽  
Author(s):  
Salma Ben-Salem ◽  
Varadha Balaji Venkadakrishnan ◽  
Hannelore V Heemers
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Control Cell ◽  
Basic Knowledge ◽  
Cell Cycle Regulators ◽  
Prostate Cell

Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced in the clinic over the past decade each eventually induce resistance for which the molecular basis is diverse. Both initiation and progression of CaP have been associated with enhanced cell proliferation and cell cycle dysregulation. A better understanding of the specific pro-proliferative molecular shifts that control cell division and proliferation during CaP progression may ultimately overcome treatment resistance. Here, we examine literature for support of this possibility. We start by reviewing recently renewed insights in prostate cell types and their proliferative and oncogenic potential. We then provide an overview of the basic knowledge on the molecular machinery in charge of cell cycle progression and its regulation by well-recognized drivers of CaP progression such as androgen receptor and retinoblastoma protein. In this respect, we pay particular attention to interactions and reciprocal interplay between cell cycle regulators and androgen receptor. Somatic alterations that impact the cell cycle-associated and -regulated genes encoding p53, PTEN and MYC during progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP are discussed. We considered also non-genomic events that impact cell cycle determinants, including transcriptional, epigenetic and micro-environmental switches that occur during CaP progression. Finally, we evaluate the therapeutic potential of cell cycle regulators, and address challenges and limitations approaches modulating their action, for CaP treatment.

Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 277-277
Author(s):  
Sankar N. Maity ◽  
Guanglin Wu ◽  
Jing-Fang Lu ◽  
Anh Hoang ◽  
Yosef Landesman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Suppressors ◽  
Nuclear Export ◽  
Small Cell ◽  
Nuclear Accumulation ◽  
Cell Cycle Regulators ◽  
Castration Resistant ◽  
Cargo Proteins

277 Background: Androgen deprivation, anti-androgen and androgen biosynthesis inhibitor treatment can initially control the metastatic prostate cancer (PCa), but treatment-refractory progression frequently follows, with the loss of tumor suppressors (TSPs) and increased expression of cell cycle proteins. Inhibition of the nuclear export protein, Exportin 1 (XPO1) leads to nuclear accumulation of cargo proteins such as TSPs & cell-cycle regulators implicated in castration-resistant PCa (CRPC) progression. XPO1 and specific cargo genes are overexpressed in metastatic CRPC relative to benign & primary prostate tumors, implicating XPO1 activity as playing a role in disease progression. Selinexor (KPT-330), a novel, oral SINE currently in Phase 1/2 for both hematological and solid tumors, has potent activity against CRPC. We hypothesized this activity is due selinexor induced nuclear expression of TSPs. Methods: To test this hypothesis, we treated selected PCa cell lines and patient-derived xenografts (PDXs, two adenocarcinomas and one small cell carcinonoma) with selinexor to determine the effect on survival and cargo protein localization. Results: Treatment with selinexor markedly inhibited PCa cell proliferation in vitro, activated the tumor suppressor TP53 & inhibited cell-cycle regulators. Also, treatment of the PDXs with selinexor for at least 3 weeks significantly inhibited tumor growth & reduced the prostate-specific antigen level in the adenocarcinomas. Selinexor increased cell death in all three PDX tumors and reduced cell proliferation in the adenocarcinomas, but not in the small-cell tumor. Expression analyses demonstrated that selinexor induced nuclear accumulation of different cargo proteins unique to the PCa model, accounting for PDX-specific regression. Conclusions: These results point to an anti-tumorigenic effect of selinexor treatment across a spectrum of hormone-refractory PCa that may provide insight into the drivers of PCa treatment resistance and heterogeneity.

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