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1.
Cancers (Basel) ; 12(7)2020 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-32708219

RESUMEN

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

2.
J Biol Chem ; 294(22): 8711-8712, 2019 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-31152093

RESUMEN

The androgen receptor (AR) is tightly linked to prostate cancer, but the mechanisms by which AR transactivation is dysregulated during cancer progression are not fully explored. Dagar et al. examined AR translocation to the nucleus to identify a link between heat shock protein 90 (HSP90) and protein kinase A (PKA). Their findings provide a potential mechanism of the initiation of AR transactivation and potential targets for developing and refining treatments for prostate cancer.


Asunto(s)
Neoplasias de la Próstata , Receptores Androgénicos , Proteínas Quinasas Dependientes de AMP Cíclico , Proteínas HSP90 de Choque Térmico , Humanos , Masculino , Fosforilación
3.
ACS Pharmacol Transl Sci ; 2(6): 453-467, 2019 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-32259077

RESUMEN

Inhibition of the androgen receptor (AR) is the mainstay treatment for advanced prostate cancer. Ralaniten (formally EPI-002) prevents AR transcriptional activity by binding to its N-terminal domain (NTD) which is essential for transcriptional activity. Ralaniten acetate (EPI-506) the triacetate pro-drug of ralaniten, remains the only AR-NTD inhibitor to have entered clinical trials (NCT02606123). While well tolerated, the trial was ultimately terminated due to poor pharmacokinetic properties and resulting pill burden. Here we discovered that ralaniten was glucuronidated which resulted in decreased potency. Long-term treatment of prostate cancer cells with ralaniten results in upregulation of UGT2B enzymes with concomitant loss of potency. This has proven to be a useful model with which to facilitate the development of more potent second-generation AR-NTD inhibitors. Glucuronidated metabolites of ralaniten were also detected in the serum of patients in Phase 1 clinical trials. Therefore, we tested an analogue of ralaniten (EPI-045) which was resistant to glucuronidation and demonstrated superiority to ralaniten in our resistant model. These data support that analogues of ralaniten designed to mitigate glucuronidation may optimize clinical responses to AR-NTD inhibitors.

4.
Structure ; 26(1): 4-6, 2018 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-29298412

RESUMEN

The transcriptional activity of the androgen receptor is tightly regulated by an intrinsically disordered N-terminal transactivation domain. In this issue of Structure, De Mol et al. (2018) identify a motif in the disordered transactivation domain that can be induced to adopt a helical conformation essential for interaction with the transcriptional machinery.


Asunto(s)
Receptores Androgénicos , Transducción de Señal , Regulación de la Expresión Génica , Unión Proteica , Activación Transcripcional
5.
J Biol Chem ; 291(42): 22231-22243, 2016 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-27576691

RESUMEN

Androgen receptor (AR) is a validated drug target for all stages of prostate cancer including metastatic castration-resistant prostate cancer (CRPC). All current hormone therapies for CRPC target the C-terminal ligand-binding domain of AR and ultimately all fail with resumed AR transcriptional activity. Within the AR N-terminal domain (NTD) is activation function-1 (AF-1) that is essential for AR transcriptional activity. Inhibitors of AR AF-1 would potentially block most AR mechanisms of resistance including constitutively active AR splice variants that lack the ligand-binding domain. Here we provide evidence that sintokamide A (SINT1) binds AR AF-1 region to specifically inhibit transactivation of AR NTD. Consistent with SINT1 targeting AR AF-1, it attenuated transcriptional activities of both full-length AR and constitutively active AR splice variants, which correlated with inhibition of growth of enzalutamide-resistant prostate cancer cells expressing AR splice variants. In vivo, SINT1 caused regression of CRPC xenografts and reduced expression of prostate-specific antigen, a gene transcriptionally regulated by AR. Inhibition of AR activity by SINT1 was additive to EPI-002, a known AR AF-1 inhibitor that is in clinical trials (NCT02606123). This implies that SINT1 binds to a site on AF-1 that is unique from EPI. Consistent with this suggestion, these two compounds showed differences in blocking AR interaction with STAT3. This work provides evidence that the intrinsically disordered NTD of AR is druggable and that SINT1 analogs may provide a novel scaffold for drug development for the treatment of prostate cancer or other diseases of the AR axis.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Neoplasias , Neoplasias de la Próstata , Pirrolidinonas/farmacología , Receptores Androgénicos/biosíntesis , Activación Transcripcional/efectos de los fármacos , Animales , Línea Celular Tumoral , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Dominios Proteicos , Pirrolidinonas/farmacocinética , Factor de Transcripción STAT3/metabolismo
6.
JCI Insight ; 1(11)2016 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-27525313

RESUMEN

Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD-targeted (AR LBD-targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V-positive lesions to determine whether they will benefit from further AR LBD-targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC.

7.
PLoS One ; 9(11): e112175, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25401462

RESUMEN

The neural retina is a critical component of the visual system, which provides the majority of sensory input in humans. Various retinal degenerative diseases can result in the permanent loss of retinal neurons, especially the light-sensing photoreceptors and the centrally projecting retinal ganglion cells (RGCs). The replenishment of lost RGCs and the repair of optic nerve damage are particularly challenging, as both RGC specification and their subsequent axonal growth and projection involve complex and precise regulation. To explore the developmental potential of pluripotent stem cell-derived neural progenitors, we have established mouse iPS cells that allow cell lineage tracing of progenitors that have expressed Atoh7/Math5, a bHLH transcription factor required for RGC production. These Atoh7 lineage reporter iPS cells encode Cre to replace one copy of the endogenous Atoh7 gene and a Cre-dependent YFP reporter in the ROSA locus. In addition, they express pluripotent markers and are capable of generating teratomas in vivo. Under anterior neural induction and neurogenic conditions in vitro, the Atoh7-Cre/ROSA-YFP iPS cells differentiate into neurons that co-express various RGC markers and YFP, indicating that these neurons are derived from Atoh7-expressing progenitors. Consistent with previous in vivo cell lineage studies, the Atoh7-Cre/ROSA-YFP iPS cells also give rise to a subset of Crx-positive photoreceptor precursors. Furthermore, inhibition of Notch signaling in the iPSC cultures results in a significant increase of YFP-positive RGCs and photoreceptor precursors. Together, these results show that Atoh7-Cre/ROSA-YFP iPS cells can be used to monitor the development and survival of RGCs and photoreceptors from pluripotent stem cells.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular/genética , Linaje de la Célula/genética , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas del Tejido Nervioso/genética , Células Fotorreceptoras/citología , Células Ganglionares de la Retina/citología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores , Expresión Génica , Genes Reporteros , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Células Fotorreceptoras/metabolismo , Células Ganglionares de la Retina/metabolismo
8.
PLoS One ; 9(9): e107991, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25268119

RESUMEN

Androgen ablation therapy causes a temporary reduction in tumor burden in patients with advanced prostate cancer. Unfortunately the malignancy will return to form lethal castration-recurrent prostate cancer (CRPC). The androgen receptor (AR) remains transcriptionally active in CRPC in spite of castrate levels of androgens in the blood. AR transcriptional activity resides in its N-terminal domain (NTD). Possible mechanisms of continued AR transcriptional activity may include, at least in part, expression of constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD). Current therapies that target the AR LBD, would not be effective against these AR variants. Currently no drugs are clinically available that target the AR NTD which should be effective against these AR variants as well as full-length AR. Niphatenones were originally isolated and identified in active extracts from Niphates digitalis marine sponge. Here we begin to characterize the mechanism of niphatenones in blocking AR transcriptional activity. Both enantiomers had similar IC50 values of 6 µM for inhibiting the full-length AR in a functional transcriptional assay. However, (S)-niphatenone had significantly better activity against the AR NTD compared to (R)-niphatenone. Consistent with niphatenones binding to and inhibiting transactivation of AR NTD, niphatenones inhibited AR splice variant. Niphatenone did not affect the transcriptional activity of the related progesterone receptor, but slightly decreased glucocorticoid receptor (GR) activity and covalently bound to GR activation function-1 (AF-1) region. Niphatenone blocked N/C interactions of AR without altering either AR protein levels or its intracellular localization in response to androgen. Alkylation with glutathione suggests that niphatenones are not a feasible scaffold for further drug development.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos Hormonales/farmacología , Éteres de Glicerilo/farmacología , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Masculino , Metribolona/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Estructura Terciaria de Proteína , Receptores Androgénicos/química , Receptores Androgénicos/fisiología , Estereoisomerismo , Activación Transcripcional/efectos de los fármacos
9.
J Clin Invest ; 123(7): 2948-60, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23722902

RESUMEN

Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos Hormonales/farmacología , Compuestos de Bencidrilo/farmacología , Clorhidrinas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Animales , Antineoplásicos Hormonales/química , Compuestos de Bencidrilo/química , Células COS , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Clorhidrinas/química , Química Clic , Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Humanos , Luciferasas/biosíntesis , Luciferasas/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Orquiectomía , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Unión Proteica , Estructura Terciaria de Proteína , Receptores Androgénicos/química , Receptores Androgénicos/genética , Estereoisomerismo , Activación Transcripcional/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Mol Cancer Ther ; 12(5): 621-31, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23443807

RESUMEN

Androgen receptor is a ligand-activated transcription factor and a validated drug target for all stages of prostate cancer. Antiandrogens compete with physiologic ligands for androgen receptor ligand-binding domain (LBD). High-throughput screening of a marine natural product library for small molecules that inhibit androgen receptor transcriptional activity yielded the furanoditerpenoid spongia-13(16),-14-dien-19-oic acid, designated terpene 1 (T1). Characterization of T1 and the structurally related semisynthetic analogues (T2 and T3) revealed that these diterpenoids have antiandrogen properties that include inhibition of both androgen-dependent proliferation and androgen receptor transcriptional activity by a mechanism that involved competing with androgen for androgen receptor LBD and blocking essential N/C interactions required for androgen-induced androgen receptor transcriptional activity. Structure-activity relationship analyses revealed some chemical features of T1 that are associated with activity and yielded T3 as the most potent analogue. In vivo, T3 significantly reduced the weight of seminal vesicles, which are an androgen-dependent tissue, thereby confirming the on-target activity of T3. The ability to create analogues of diterpenoids that have varying antiandrogen activity represents a novel class of chemical compounds for the analysis of androgen receptor ligand-binding properties and therapeutic development.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Diterpenos/farmacología , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Andrógenos/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diterpenos/química , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Receptores Androgénicos/química , Transcripción Genética
11.
J Med Chem ; 55(1): 503-14, 2012 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-22148427

RESUMEN

Extracts of the marine sponge Niphates digitalis collected in Dominica showed strong activity in a cell-based assay designed to detect antagonists of the androgen receptor (AR) that could act as lead compounds for the development of a new class of drugs to treat castration recurrent prostate cancer (CRPC). Assay-guided fractionation showed that niphatenones A (3) and B (4), two new glycerol ether lipids, were the active components of the extracts. The structures of 3 and 4 were elucidated by analysis of NMR and MS data and confimed via total synthesis. Biological evaluation of synthetic analogues of the niphatenones has shown that the enantiomers 7 and 8 are more potent than the natural products in the screening assay and defined preliminary SAR for the new AR antagonist pharmacophore, including the finding that the Michael acceptor enone functionality is not required for activity. Niphatenone B (4) and its enantiomer 8 blocked androgen-induced proliferation of LNCaP prostate cancer cells but had no effect on the proliferation of PC3 prostate cancer cells that do not express functional AR, consistent with activity as AR antagonists. Use of the propargyl ether 44 and Click chemistry showed that niphatenone B binds covalently to the activation function-1 (AF1) region of the AR N-terminus domain (NTD).


Asunto(s)
Antineoplásicos/química , Éteres de Glicerilo/química , Poríferos/química , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Animales , Antineoplásicos/síntesis química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Éteres de Glicerilo/síntesis química , Éteres de Glicerilo/aislamiento & purificación , Éteres de Glicerilo/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Conformación Molecular , Neoplasias de la Próstata/tratamiento farmacológico , Estereoisomerismo , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacos
12.
Cancer Res ; 69(8): 3433-42, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19351846

RESUMEN

Identification of gene expression signatures associated with metastases provides a tool to discern mechanisms and potential therapeutic targets and may lead toward a molecular classification system in pathology. Prostate cancer (CaP) frequently metastasizes to the bone to form osteoblastic lesions. Correlative clinical data and in vitro evidence have led to the hypothesis that osteoblast-derived factors promote hormonal progression of CaP cells. Here, the gene expression signature of CaP exposed to osteoblast-derived factors was identified. This signature included known androgen-regulated genes, oncogenes, tumor suppressors, and genes whose products are involved in apoptosis and cell cycle. A comparative functional genomic approach involved the application of this responsive gene expression signature to clinical samples of human CaP, melanomas, and oral cancers. Cluster analysis revealed that this gene expression signature had specificity for CaP and could resolve clinical specimens according to stage (benign, localized, and metastatic) and androgen sensitivity with an accuracy of 100% and 80%, respectively. Together, these results suggest that factors derived from osteoblasts induce a more advanced phenotype of CaP and promotes hormonal progression.


Asunto(s)
Neoplasias Óseas/genética , Neoplasias Hormono-Dependientes/genética , Osteoblastos/metabolismo , Neoplasias de la Próstata/genética , Animales , Neoplasias Óseas/secundario , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Neoplasias Hormono-Dependientes/metabolismo , Neoplasias Hormono-Dependientes/patología , Osteoblastos/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Extractos de Tejidos/farmacología , Trasplante Heterólogo
13.
Exp Hematol ; 35(8): 1293-302, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17562354

RESUMEN

OBJECTIVE: We previously demonstrated that c-kit expression decreases during murine embryonic stem cell (ESC) differentiation induced by leukemia inhibitory factor removal. In this study, we addressed the possibility that c-kit is a marker of undifferentiated murine ESC and, moreover, that it plays a role in maintaining the undifferentiated state of these cells. MATERIALS AND METHODS: c-kit expression was analyzed under various differentiation conditions by flow cytometry and quantitative reverse transcription polymerase chain reaction. ESC were then sorted on the basis of c-kit expression and functionality was investigated using embryoid body and colony-forming cell assays. Imatinib (Gleevec) and ACK2 were used to block, and stem cell factor was used to stimulate, c-kit activity. RESULTS: c-kit expression decreased in two murine ESC lines under various differentiation conditions. Sorting of ESC populations on the basis of c-kit expression revealed significant differences in the functional capacities and gene expression profiles of the sorted populations. The inhibition studies revealed an important role for tyrosine kinase activity in maintaining ESC viability and differentiation capacity, at least in part by preventing apoptosis and enhancing cell cycle progression. However, activation of c-kit alone is not sufficient for maintaining undifferentiated ESC. CONCLUSION: The results suggest that c-kit may represent a useful marker for monitoring ESC functionality. Moreover, tyrosine kinase signaling plays an important role in maintaining undifferentiated ESC. This work provides valuable insights into the complex signaling pathways that synergize to maintain the undifferentiated state of murine ESC.


Asunto(s)
Células Madre Embrionarias/fisiología , Proteínas Tirosina Quinasas/fisiología , Animales , Técnicas de Cultivo de Célula , Ciclo Celular/fisiología , Diferenciación Celular , Ensayo de Unidades Formadoras de Colonias , Cartilla de ADN , Células Madre Embrionarias/citología , Citometría de Flujo , Ratones , Proteínas Proto-Oncogénicas c-kit/genética , Transducción de Señal , Transcripción Genética
14.
Exp Hematol ; 35(4): 627-39, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17379073

RESUMEN

OBJECTIVE: Dendritic cells (DC) play a critical role in establishment and maintenance of central and peripheral tolerance. Despite intensive research, our knowledge of the molecular mechanisms regulating DC development and function is limited, thus hindering our ability to generate appropriate DC populations for manipulating immune tolerance. We utilized mice deficient in the SH2-containing inositol-5-phosphatase (SHIP) to examine the role of cytokine signaling in DC development and function. METHODS: We analyzed the phenotype of both primary and bone marrow (BM)-derived DC (BMDC) using flow cytometry. In addition, cytokine production was measured using cytometric bead arrays and the ability of DC to induce allogeneic T-cell proliferation was assessed using thymidine incorporation assays. RESULTS: We demonstrated that spleen DC isolated from SHIP-deficient mice are increased in number and have an altered phenotype. In vitro analyses revealed that SHIP-deficient BM cells give rise to a higher frequency of myeloid, but not plasmacytoid, DC due to both an increased progenitor frequency and enhanced cytokine sensitivity. The BMDC exhibit an altered phenotype that correlates with a reduced capacity to induce allogeneic T-cell proliferation. Addition of interleukin-6 to WT BM cultures during DC differentiation partially induces a KO phenotype. CONCLUSION: These studies suggest that myeloid and plasmacytoid DC progenitors are differentially sensitive to signaling pathways in which SHIP is involved. Moreover, they suggest that interleukin-6 may have an important role in regulating the phenotype and function of myeloid DC.


Asunto(s)
Células Dendríticas/inmunología , Monoéster Fosfórico Hidrolasas/inmunología , Animales , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Inositol Polifosfato 5-Fosfatasas , Interleucina-4/administración & dosificación , Ratones , Ratones Noqueados
15.
Cancer Res ; 65(7): 2947-55, 2005 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-15805298

RESUMEN

Increasing evidence suggests that altered immune function accompanies, and indeed may facilitate, cancer progression. In this study, we sought to determine the nature of, and cellular mechanisms underlying, changes in immune status during disease progression in a transgenic mouse model of prostate dysplasia. Immune cells in the tumor microenvironment, as well as in the secondary lymphoid tissues, displayed altered phenotypes. Although evidence of antitumor immunity was detected, there was a paradoxical decrease in the ability of T cells to proliferate in vitro at later stages of disease progression. Detailed analysis of the draining lumbar lymph nodes revealed an increased frequency and number of CD4(+)CD25(+) T cells and an enhanced production of inhibitory cytokines, which correlated with impaired T-cell function. Functional studies confirmed a role for CD4(+)CD25(+) regulatory T cells in suppressing T-cell proliferation as well as regulating the growth of transplanted prostate tumor cells. In addition, our studies show for the first time that anti-CD25 antibody treatment reduces, but does not prevent, tumor growth in a transgenic mouse model of prostate dysplasia. Taken together, this work provides compelling evidence that prostate tumor progression is accompanied by altered immune function and, moreover, that regulatory T cells play an important role in this process. These studies thus provide the impetus for development of specific and effective strategies to deplete regulatory T cells, or suppress their function, as an alternative or adjunct strategy for reducing tumor growth.


Asunto(s)
Próstata/inmunología , Próstata/patología , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Tejido Linfoide/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Interleucina-2/inmunología , Linfocitos T/inmunología
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