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1.
Mol Oncol ; 16(13): 2518-2536, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34919781

RESUMO

Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naïve-advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq datasets and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity and that this repressive function could be pathologically abrogated by AR variants in PCa.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Androgênios , Linhagem Celular Tumoral , Plasticidade Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo
3.
Hypertension ; 77(4): 1029-1035, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33583200

RESUMO

The General Data Protection Regulation (GDPR) became binding law in the European Union Member States in 2018, as a step toward harmonizing personal data protection legislation in the European Union. The Regulation governs almost all types of personal data processing, hence, also, those pertaining to biomedical research. The purpose of this article is to highlight the main practical issues related to data and biological sample sharing that biomedical researchers face regularly, and to specify how these are addressed in the context of GDPR, after consulting with ethics/legal experts. We identify areas in which clarifications of the GDPR are needed, particularly those related to consent requirements by study participants. Amendments should target the following: (1) restricting exceptions based on national laws and increasing harmonization, (2) confirming the concept of broad consent, and (3) defining a roadmap for secondary use of data. These changes will be achieved by acknowledged learned societies in the field taking the lead in preparing a document giving guidance for the optimal interpretation of the GDPR, which will be finalized following a period of commenting by a broad multistakeholder audience. In parallel, promoting engagement and education of the public in the relevant issues (such as different consent types or residual risk for re-identification), on both local/national and international levels, is considered critical for advancement. We hope that this article will open this broad discussion involving all major stakeholders, toward optimizing the GDPR and allowing a harmonized transnational research approach.


Assuntos
Pesquisa Biomédica , Segurança Computacional , Registros de Saúde Pessoal/ética , Disseminação de Informação , Pesquisa Biomédica/ética , Pesquisa Biomédica/legislação & jurisprudência , Segurança Computacional/legislação & jurisprudência , Segurança Computacional/tendências , Europa (Continente) , Humanos , Disseminação de Informação/legislação & jurisprudência , Disseminação de Informação/métodos
4.
Biol Aujourdhui ; 214(3-4): 137-148, 2020.
Artigo em Francês | MEDLINE | ID: mdl-33357372

RESUMO

Founded in 1919, the Society of Biology of Strasbourg (SBS) is a learned society whose purpose is the dissemination and promotion of scientific knowledge in biology. Subsidiary of the Society of Biology, the SBS celebrated its Centenary on Wednesday, the 16th of October 2019 on the Strasbourg University campus and at the Strasbourg City Hall. This day allowed retracing the various milestones of the SBS, through its main strengths, its difficulties and its permanent goal to meet scientific and societal challenges. The common thread of this day was the transmission of knowledge related to the past, the present, but also the future. At the start of the 21st century, the SBS must continue to reinvent itself to pursue its objective of transmitting scientific knowledge in biology and beyond. Scientific talks performed by senior scientists and former SBS thesis prizes awardees, a round table, and informal discussions reflected the history and the dynamism of the SBS association. All SBS Centennial participants have set the first milestone for the SBS Bicentennial.


TITLE: La Société de Biologie de Strasbourg : 100 ans au service de la science et de la société. ABSTRACT: Filiale de la Société de Biologie, la Société de Biologie de Strasbourg (SBS) est une société savante qui a pour objet la diffusion et la promotion du savoir scientifique en biologie et en médecine. Fondée en 1919, La SBS a célébré son Centenaire le mercredi 16 octobre 2019. Cette journée a permis de retracer les différents jalons de la SBS, à travers ses lignes de forces, ses difficultés et sa volonté permanente de mettre en exergue les défis scientifiques et sociétaux auxquels participent les recherches strasbourgeoises. Le fil rouge de cette journée a été la transmission d'un savoir en lien avec le passé, le présent, mais également le futur. En ce début du 21e siècle, la SBS se doit de continuer de se réinventer pour poursuivre son objectif de transmission des connaissances scientifiques en biologie et au-delà. L'ensemble des participants du Centenaire de la SBS a ainsi posé la première pierre du Bicentenaire de la SBS.


Assuntos
Biologia , Sociedades Científicas , Biologia/ética , História do Século XX , História do Século XXI , Humanos , Conhecimento , Sociedades Científicas/história
6.
Am J Hum Genet ; 104(2): 319-330, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639322

RESUMO

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação Puntual , Fatores de Transcrição/genética , Alelos , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Camundongos , Síndrome , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
7.
Oncotarget ; 8(42): 72008-72020, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-29069764

RESUMO

Constitutively active androgen receptor (AR) variants have been involved in the expression of mesenchymal markers such as N-cadherin in prostate cancer (PCa). However, the underlying molecular mechanisms remain elusive. It remains unclear, whether N-cadherin gene (CDH2) is a direct transcriptional target of AR variants or whether the observed upregulation is due to indirect effects through additional regulatory factors. Moreover, the specific contribution of full-length AR and AR variants in N-cadherin regulation in PCa has never been explored deeply. To investigate this, we artificially mimicked the co-expression of AR variants together with a full-length AR and performed miRNA-seq, RNA-seq and ChIP assays. Our results were in favor of a direct AR variants action on CDH2. Our data also revealed a distinctive mode of action between full-length AR and AR variants to regulate N-cadherin expression. Both wild type AR and AR variants could interact with a regulatory element in intron 1 of CDH2. However, a higher histone H4 acetylation in this genomic region was only observed with AR variants. This suggests that full-length AR may play an occluding function to impede CDH2 upregulation. Our data further highlighted a negative effect of AR variants on the expression of the endogenous full-length AR in LNCaP. These differences in the mode of action of AR variants and full-length AR for the control of one key gene for prostate cancer progression could be worth considering for targeting AR variants in PCa.

8.
Med Sci (Paris) ; 33(8-9): 758-764, 2017.
Artigo em Francês | MEDLINE | ID: mdl-28945566

RESUMO

Prostate cancer is a public health concern as it currently represents the most frequent malignancy in men in Europe. Progression of this hormone-dependent cancer is driven by androgens. Thus, the most common treatment for patients with advanced prostate cancer consists in an androgen ablation by castration therapy. However, the majority of patients relapses and develops a castration-resistant prostate cancer. This failure of androgen deprivation is related to the emergence of mutant and splice variants of the androgen receptor. Indeed, androgen receptor variants are ligand-independent, constitutively active and thus able to induce resistance to castration. This review focuses on AR variants signaling pathways and their role in resistance to castration and prostate cancer progression.


Assuntos
Polimorfismo Genético , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Castração , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Transdução de Sinais/genética
10.
Ann Biol Clin (Paris) ; 74(2): 227-32, 2016.
Artigo em Francês | MEDLINE | ID: mdl-27029727

RESUMO

To systematically review the evidence for the use of PSA and other biomarkers in the early detection of prostate cancer, we searched PubMed for clinical trials and studies assessing PSA and other biomarkers in the early detection of prostate cancer, published between 2000 and May 2013 that included >200 subjects. The level of evidence (LOE) for clinical utility was evaluated using the tumor marker utility grading system. A total of 84 publications, corresponding to 70 trials and studies were selected for inclusion in this review. We attributed a level of evidence (LoE) of IA to PSA for early PCa detection, but we do not recommend its use in mass screening. Emerging biomarkers were assessed in prospective case-control and cohort studies: PCA3 (n=3); kallikreins (n=3); [-2]proPSA (n=5); fusion oncogenes (n=2). These studies used biopsy results for prostate cancer to determine specificity and sensitivity, but they did not assess the effect on PCa mortality. The LoE attributed was III-C. PSA can be used for early prostate cancer detection but mass screening is not recommended. Studies on other biomarkers suggest that they could be used, individually or in combination, to improve the selection of patients with elevated PSA levels for biopsy, but RCTs assessing their impact on prostate cancer management and mortality are needed. A better use of available tests is possible for men at risk in order to maximize the risk-benefit ratio.


Assuntos
Biomarcadores Tumorais/análise , Detecção Precoce de Câncer/métodos , Neoplasias da Próstata/diagnóstico , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer/normas , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/normas , Antígeno Prostático Específico/análise , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/epidemiologia , Sensibilidade e Especificidade
11.
Oncotarget ; 7(43): 69397-69411, 2016 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-26993766

RESUMO

Despite the advent of several new treatment options over the past years, advanced/metastatic prostate carcinoma (PCa) still remains incurable, which justifies the search for novel targets and therapeutic molecules. Nucleophosmin (NPM1) is a shuttling nucleoprotein involved in tumor growth and its targeting could be a potential approach for cancer therapy. We previously demonstrated that the multivalent pseudopeptide N6L binds to NPM1 potently affecting in vitro and in vivo tumor cell growth of various tumor types as well as angiogenesis. Furthermore, NPM1 binds to androgen receptor (AR) and modulate its activity. In this study, we first investigated the implication of the NPM1 and its Thr199 and Thr234/237 phosphorylated forms in PCa. We showed that phosphorylated forms of NPM1 interact with androgen receptor (AR) in nucleoplasm. N6L treatment of prostate tumor cells led to inhibition of NPM1 phosphorylation in conjunction with inhibition of AR activity. We also found that total and phosphorylated NPM1 were overexpressed in castration-resistant PCa. Assessment of the potential therapeutic role of N6L in PCa indicated that N6L inhibited tumor growth both in vitro and in vivo when used either alone or in combination with the standard-of-care first- (hormonotherapy) and second-line (docetaxel) treatments for advanced PCa. Our findings reveal the role of Thr199 and Thr234/237 phosphorylated NPM1 in PCa progression and define N6L as a new drug candidate for PCa therapy.


Assuntos
Proteínas Nucleares/metabolismo , Nucleoproteínas/antagonistas & inibidores , Peptídeos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Docetaxel , Humanos , Masculino , Camundongos Nus , Nucleofosmina , Nucleoproteínas/metabolismo , Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Ligação Proteica , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Treonina/metabolismo , Carga Tumoral/efeitos dos fármacos
12.
Mol Cell Endocrinol ; 422: 182-191, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26586211

RESUMO

The skeleton is the preferred site for prostate cancer (PC) metastasis leading to incurable castration-resistant disease. The increased expression of genes encoding steroidogenic enzymes found in bone metastatic tissue from patients suggests that up-regulated steroidogenesis might contribute to tumor growth at the metastatic site. Because of the overall sclerotic phenotype, we hypothesize that osteoblasts regulate the intratumoral steroidogenesis of castration resistant prostate cancer (CRPC) in bone. We here show that osteoblasts alter the steroidogenic transcription program in CRPC cells, closely mimicking the gene expression pattern described in CRPC. Osteoblast-stimulated LNCaP-19 cells displayed an increased expression of genes encoding for steroidogenic enzymes (CYP11A1, HSD3B1, and AKR1C3), estrogen signaling-related genes (CYP19A1, and ESR2), and genes for DHT-inactivating enzymes (UGT2B7, UGT2B15, and UGT2B17). The observed osteoblast-induced effect was exclusive to osteogenic CRPC cells (LNCaP-19) in contrast to osteolytic PC-3 and androgen-dependent LNCaP cells. The altered steroid enzymatic pattern was specific for the intratibial tumors and verified by immunohistochemistry in tissue specimens from LNCaP-19 xenograft tumors. Additionally, the overall steroidogenic effect was reflected by corresponding levels of progesterone and testosterone in serum from castrated mice with intratibial xenografts. A bi-directional interplay was demonstrated since both proliferation and Esr2 expression of osteoblasts were induced by CRPC cells in steroid-depleted conditions. Together, our results demonstrate that osteoblasts are important mediators of the intratumoral steroidogenesis of CRPC and for castration-resistant growth in bone. Targeting osteoblasts may therefore be important in the development of new therapeutic approaches.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Osteoblastos/citologia , Neoplasias de Próstata Resistentes à Castração/patologia , Esteroides/biossíntese , Androgênios/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células , Meios de Cultivo Condicionados/química , Receptor beta de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Células NIH 3T3 , Transplante de Neoplasias , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo
13.
Chembiochem ; 15(16): 2370-3, 2014 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-25212277

RESUMO

Most of the biological effects of androgen hormones are mediated through an intracellular transcription factor, the androgen receptor (AR). This protein presents a long disordered N-terminal domain (NTD), known to aggregates into amyloid fibers.1 This aggregation property is usually associated with the presence of a poly-glutamine tract (polyQ), known to be involved in several pathologies.2 The NTD has gain interest recently because potential anti-prostate-cancer molecules could target this domain.3 Here, we characterize a conserved region of the NTD (distal from polyQ); it promotes the formation of amyloid fibers under mild oxidative conditions. Unlike most fibrils, which are irreversibly aggregated, the free peptides can be restored from the fibril by the addition of a reducing agent.


Assuntos
Amiloide/química , Receptores Androgênicos/química , Sequência de Aminoácidos , Dicroísmo Circular , Dimerização , Humanos , Masculino , Microscopia Eletrônica , Dados de Sequência Molecular , Peptídeos/química , Estrutura Secundária de Proteína , Receptores Androgênicos/metabolismo
14.
Neoplasia ; 15(7): 761-72, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23814488

RESUMO

Castration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand-dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo, with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance.


Assuntos
Caderinas/metabolismo , Transdiferenciação Celular , Resistencia a Medicamentos Antineoplásicos , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Androgênios/metabolismo , Antineoplásicos/farmacologia , Caderinas/genética , Linhagem Celular Tumoral , Transdiferenciação Celular/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Masculino , Fenótipo , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Ativação Transcricional
15.
PLoS One ; 8(5): e63466, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23658830

RESUMO

Androgen receptor (AR) signaling pathway remains the foremost target of novel therapeutics for castration-resistant prostate cancer (CRPC). However, the expression of constitutively active AR variants lacking the carboxy-terminal region in CRPC may lead to therapy inefficacy. These AR variants are supposed to support PCa cell growth in an androgen-depleted environment, but their mode of action still remains unresolved. Moreover, recent studies indicate that constitutively active AR variants are expressed in primary prostate tumors and may contribute to tumor progression. The aim of this study was to investigate the impact of constitutively active AR variants on the expression of tumor progression markers. N-cadherin expression was analyzed in LNCaP cells overexpressing the wild type AR or a constitutively active AR variant by qRT-PCR, Western blot and immunofluorescence. We showed here for the first time that N-cadherin expression was increased in the presence of constitutively active AR variants. These results were confirmed in C4-2B cells overexpressing these AR variants. Although N-cadherin expression is often associated with a downregulation of E-cadherin, this phenomenon was not observed in our model. Nevertheless, in addition to the increased expression of N-cadherin, an upregulation of other mesenchymal markers expression such as VIMENTIN, SNAIL and ZEB1 was observed in the presence of constitutively active variants. In conclusion, our findings highlight novel consequences of constitutively active AR variants on the regulation of mesenchymal markers in prostate cancer.


Assuntos
Biomarcadores Tumorais/genética , Variação Genética , Mesoderma/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Regulação para Cima , Caderinas/genética , Linhagem Celular Tumoral , Progressão da Doença , Proteínas de Homeodomínio/genética , Humanos , Masculino , Fatores de Transcrição/genética , Vimentina/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco
16.
Cell Biol Int ; 37(5): 464-70, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23418075

RESUMO

We have investigated the expression of prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) transcripts in androgen-dependent (LNCaP) and androgen-independent (22Rv1) prostate cancer cell lines. We also enquired whether Q640X CTE-truncated androgen receptor (AR) has an impact on transcription of mRNA for PSMA and PSA in transfected androgen-sensitive prostate cancer LNCaP cells. Wild type LNCaP, 22Rv1 prostate cancer cells, prostate stromal cells (PrSC) and LNCaP cells transfected with p-Q640X AR, p-WT AR or p-C3 empty plasmids were studied. The expression of PSMA and PSA were detected by real-time PCR after transfection for 4 and 7 days. Expression of mRNAs for PSA was sixfold greater than PSMA in wild type LNCaP cells. In contrast, the wild type androgen refractory 22Rv1 cell line reacted almost exactly the opposite way reverse to LNCaP cells, since the transcription of mRNA for PSMA almost twofold greater than PSA. Non-transfected human PrSC responded similarly to PSMA mRNA and PSA mRNA was not detected in these cells. Q640X AR transfected LNCaP cells downregulated the expression of PSMA and PSA genes after 7 days. Our results demonstrate that Q640X mutated AR may have an important regulatory role in mediating the PSMA and PSA genes expression during the progression of prostate cancer from androgen-dependence to androgen-independence. Understanding their functional properties and mechanisms by which ARs involved in regulation of PSMA and PSA expression will allow the identification of new target therapies for the treatment of hormone-resistant prostate cancer.


Assuntos
Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Antígeno Prostático Específico/metabolismo , Receptores Androgênicos/metabolismo , Substituição de Aminoácidos , Antígenos de Superfície/genética , Linhagem Celular Tumoral , Regulação para Baixo , Glutamato Carboxipeptidase II/genética , Humanos , Masculino , Mutação , Fosforilação , Antígeno Prostático Específico/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Transcrição Gênica
17.
PLoS One ; 7(8): e42252, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22879924

RESUMO

Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape--frequency and delay--are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RR(intermittent): 14.5, RR(complete blockade): 6.5 and 1.35). All recurrent tumors displayed new quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.


Assuntos
Androgênios/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Androgênios/deficiência , Animais , Sequência de Bases , Castração , Análise por Conglomerados , Terapia Combinada , Intervalo Livre de Doença , Dosagem de Genes/genética , Humanos , Masculino , Camundongos , Mutação/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Tirosina Quinases/metabolismo , Receptor ErbB-2/genética , Receptores Androgênicos/genética
18.
Oncology ; 80(1-2): 1-11, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21577012

RESUMO

Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18-24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/uso terapêutico , Docetaxel , Humanos , Masculino , Neoplasias Hormônio-Dependentes/metabolismo , Orquiectomia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
19.
Endocrinology ; 152(6): 2174-83, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21486935

RESUMO

The repression of the androgen receptor (AR) activity is a major objective to inhibit prostate cancer growth. One underlying mechanism for efficient hormone therapy is based on corepressors that inactivate the AR. In line with this, castration-resistant prostate cancer is associated with malfunction or reduced corepressor action. To overcome this, the overexpression of endogenous corepressors, however, affects many other transcription factors. Therefore, an AR-specific corepressor could be of advantage. Using a yeast peptide aptamer two-hybrid screen with the full-length human AR, we identified a short amino acid-stretch that binds specifically to the human AR in yeast and in mammalian cells and not to the closely related progesterone or glucocorticoid receptors. Furthermore, fused to a silencing domain, this aptamer-based corepressor (AB-CoR) exhibits corepressor activity by inhibiting both the AR-mediated transactivation and expression of the AR target gene PSA. Furthermore, stable expression of the AB-CoR inhibits growth of human LNCaP prostate cancer cells. Moreover, we generated a cell-permeable AB-CoR by fusing a protein transduction domain to establish a vector-free transport system. Treatment of LNCaP cells with the bacterially expressed and affinity-purified cell-permeable AB-CoR peptide resulted in a significant inhibition of both AR-mediated transactivation and prostate cancer cell proliferation. Thus, generation of a novel AR-specific aptamer-based corepressor may present a vector-free inhibition of AR-dependent prostate cancer growth as a novel approach.


Assuntos
Aptâmeros de Peptídeos/farmacocinética , Proliferação de Células , Proteínas Correpressoras/metabolismo , Regulação para Baixo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/fisiopatologia , Receptores Androgênicos/metabolismo , Aptâmeros de Peptídeos/síntese química , Aptâmeros de Peptídeos/genética , Aptâmeros de Peptídeos/metabolismo , Linhagem Celular Tumoral , Proteínas Correpressoras/síntese química , Proteínas Correpressoras/genética , Proteínas Correpressoras/farmacocinética , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Permeabilidade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Ligação Proteica , Receptores Androgênicos/genética , Especificidade da Espécie , Ativação Transcricional/efeitos dos fármacos
20.
Cancer Res ; 70(3): 1225-35, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20103638

RESUMO

Castration resistance in prostate cancer (PCa) constitutes an advanced, aggressive disease with poor prognosis, associated with uncontrolled cell proliferation, resistance to apoptosis, and enhanced invasive potential. The molecular mechanisms involved in the transition of PCa to castration resistance are obscure. Here, we report that the nonselective cationic channel transient receptor potential vanilloid 2 (TRPV2) is a distinctive feature of castration-resistant PCa. TRPV2 transcript levels were higher in patients with metastatic cancer (stage M1) compared with primary solid tumors (stages T2a and T2b). Previous studies of the TRPV2 channel indicated that it is primarily involved in cancer cell migration and not in cell growth. Introducing TRPV2 into androgen-dependent LNCaP cells enhanced cell migration along with expression of invasion markers matrix metalloproteinase (MMP) 9 and cathepsin B. Consistent with the likelihood that TRPV2 may affect cancer cell aggressiveness by influencing basal intracellular calcium levels, small interfering RNA-mediated silencing of TRPV2 reduced the growth and invasive properties of PC3 prostate tumors established in nude mice xenografts, and diminished expression of invasive enzymes MMP2, MMP9, and cathepsin B. Our findings establish a role for TRPV2 in PCa progression to the aggressive castration-resistant stage, prompting evaluation of TRPV2 as a potential prognostic marker and therapeutic target in the setting of advanced PCa.


Assuntos
Neoplasias da Próstata/genética , Interferência de RNA , Canais de Cátion TRPV/genética , Androgênios/metabolismo , Androgênios/farmacologia , Animais , Western Blotting , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Microscopia Confocal , Invasividade Neoplásica , Metástase Neoplásica , Orquiectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
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