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1.
Bioorg Med Chem Lett ; 35: 127778, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422603

RESUMO

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

2.
Bioorg Med Chem Lett ; 30(12): 127204, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334911

RESUMO

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

3.
Nature ; 579(7797): 130-135, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32076273

RESUMO

Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues1,2. Although ILC2s are found in cancers of these tissues3, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8+ T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1+ TILC2s and PD-1+ T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/imunologia , Linfócitos/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Células Dendríticas/imunologia , Feminino , Humanos , Imunidade Inata/imunologia , Imunoterapia , Interleucina-33/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia
4.
Asian J Urol ; 6(1): 65-81, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30775250

RESUMO

This article describes cell signaling network of metastatic prostate cancer (PCa) to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics. The article focuses on our recent progress in the understanding of: 1) The plasticity and dynamics of tumor-stroma interaction; 2) The significance of epigenetic reprogramming in conferring cancer growth, invasion and metastasis; 3) New insights on altered junctional communication affecting PCa bone and brain metastases; 4) Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy; 5) Genetic-based therapy to co-target tumor and bone stroma; 6) PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis; 7) The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis; and 8) Characterization of imprinting cluster of microRNA, in tumor-stroma interaction. This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation. This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications. We dedicate this article in our fond memory of Dr. Donald S. Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.

5.
Prostate ; 76(3): 286-93, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26493492

RESUMO

BACKGROUND: Fyn is a kinase that is upregulated in a subset of metastatic castration-resistant prostate cancer. Saracatinib potently inhibits Fyn activation. We have noted a relationship between Fyn expression and directional motility, a cellular process related to metastasis. As such we hypothesized that treatment with saracatinib would increase the time required to develop new metastatic lesions. METHODS: Patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel were eligible for enrollment. This study was executed as a randomized discontinuation trial. During a lead-in phase of two 28-Day cycles, all patients received saracatinib. Afterward, patients with radiographically stable disease were randomized to either saracatinib or placebo. Patients continued treatment until evidence of new metastasis. RESULTS: Thirty-one patients were treated. Only 26% of patients had stable disease after 8 weeks and thus proceeded to randomization. This required early termination of the study for futility. The 70% of patients who progressed after the lead-in phase exhibited expansion of existing lesions or decompensation due to clinical progression without new metastatic lesions. Fatigue was reported in more than 25% of patients (all grades) with only two patients experiencing grade 3 toxicity. Other grade 3 adverse events included dehydration, thrombocytopenia, and weakness. CONCLUSIONS: This study was unable to determine if saracatinib had potential as metastasis inhibitor. Metastasis inhibition by saracatinib may still be viable in an earlier time in the disease history.


Assuntos
Centros Médicos Acadêmicos , Antineoplásicos/uso terapêutico , Benzodioxóis/uso terapêutico , Metástase Neoplásica/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Quinazolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Chicago , Humanos , Masculino , Pessoa de Meia-Idade
6.
Oncotarget ; 6(42): 44072-83, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26624980

RESUMO

FYN is a SRC family kinase (SFK) that has been shown to be up-regulated in human prostate cancer (PCa) tissues and cell lines. In this study, we observed that FYN is strongly up-regulated in human neuroendocrine PCa (NEPC) tissues and xenografts, as well as cells derived from a NEPC transgenic mouse model. In silico analysis of FYN expression in prostate cancer cell line databases revealed an association with the expression of neuroendocrine (NE) markers such as CHGA, CD44, CD56, and SYP. The loss of FYN abrogated the invasion of PC3 and ARCaPM cells in response to MET receptor ligand HGF. FYN also contributed to the metastatic potential of NEPC cells in two mouse models of visceral metastasis with two different cell lines (PC3 and TRAMPC2-RANKL). The activation of MET appeared to regulate neuroendocrine (NE) features as evidenced by increased expression of NE markers in PC3 cells with HGF. Importantly, the overexpression of FYN protein in DU145 cells was directly correlated with the increase of CHGA. Thus, our data demonstrated that the neuroendocrine differentiation that occurs in PCa cells is, at least in part, regulated by FYN kinase. Understanding the role of FYN in the regulation of NE markers will provide further support for ongoing clinical trials of SFK and MET inhibitors in castration-resistant PCa patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Movimento Celular , Neoplasias Hepáticas/enzimologia , Tumores Neuroendócrinos/enzimologia , Neoplasias da Próstata/enzimologia , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Animais , Biomarcadores Tumorais/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Cromogranina A/metabolismo , Simulação por Computador , Bases de Dados Genéticas , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Camundongos Endogâmicos C57BL , Camundongos SCID , Camundongos Transgênicos , Invasividade Neoplásica , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/secundário , Fenótipo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção , Carga Tumoral , Regulação para Cima
7.
Adv Exp Med Biol ; 889: 105-18, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26658999

RESUMO

microRNAs are noncoding RNAs that are important for embryonic stem cell development and epithelial to mesenchymal transition (EMT). Tumor cells hijack EMT and stemness to grow and metastasize to distant organs including bone. In the tumor microenvironment, tumor cells interact with the stromal fibroblasts at the primary and metastatic sites and this interaction leads to tumor growth, EMT, and bone metastasis. Tumor-stromal interactions are a dynamic process that involves both cell-cell communications and extracellular vesicles and soluble factors. Growing body of evidence suggests that microRNAs are part of the payload that comprises the extracellular vesicles. microRNAs induce reactive stroma and thus convert normal stroma into tumor-associated stroma to promote aggressive tumorigenicity in vitro and in vivo. Landmark published studies demonstrate that expression of specific microRNAs of DLK1-DIO3 stem cell cluster correlates with patient survival in metastatic prostate cancer. Thus, microRNAs mediate tumor growth, EMT, and metastasis through cell intrinsic mechanisms and extracellular communications and could be novel biomarkers and therapeutic targets in bone metastatic prostate cancer.


Assuntos
Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias da Próstata/genética , Microambiente Tumoral/genética , Biomarcadores Tumorais/genética , Epigênese Genética/genética , Humanos , Masculino , Modelos Genéticos , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais/genética
8.
Oncoscience ; 2(9): 743-4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26501076
9.
Clin Cancer Res ; 20(24): 6559-69, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25324143

RESUMO

PURPOSE: MicroRNAs in the delta-like 1 homolog-deiodinase, iodothyronine 3 (DLK1-DIO3) cluster have been shown to be critical for embryonic development and epithelial to mesenchymal transition (EMT). DLK1-DIO3 cluster miRNAs are elevated in the serum of patients with metastatic cancer. However, the biologic functions of these miRNAs in the EMT and metastasis of cancer cells are poorly understood. We previously demonstrated the oncogenic and metastatic role of miR-409-3p/5p, a member of this cluster, in prostate cancer. In this study, we defined the role of miR-154* and miR-379, two key members of this cluster, in prostate cancer progression and bone metastasis in both cell line models and clinical specimens. EXPERIMENTAL DESIGN: Genetic manipulation of miR-154* and miR-379 was performed to determine their role in tumor growth, EMT, and bone metastasis in mouse models. We determined the expression of miR-154* in prostate cancer clinical samples and bone metastasis samples using in situ hybridization and quantum dot labeling. RESULTS: Elevated expression of miR-154* and miR-379 was observed in bone metastatic prostate cancer cell lines and tissues, and miR-379 expression correlated with progression-free survival of patients with prostate cancer. Intracardiac inoculation (to mimic systemic dissemination) of miR-154* inhibitor-treated bone metastatic ARCaPM prostate cancer cells in mice led to decreased bone metastasis and increased survival. CONCLUSION: miR-154* and miR-379 play important roles in prostate cancer biology by facilitating tumor growth, EMT, and bone metastasis. This finding has particular translational importance because miRNAs in the DLK1-DIO3 cluster can be attractive biomarkers and possible therapeutic targets to treat bone metastatic prostate cancer.


Assuntos
Neoplasias Ósseas/secundário , Transição Epitelial-Mesenquimal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Iodeto Peroxidase/genética , Proteínas de Membrana/genética , MicroRNAs/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Proteínas de Ligação ao Cálcio , Linhagem Celular Tumoral , Modelos Animais de Doenças , Expressão Gênica , Redes Reguladoras de Genes , Xenoenxertos , Humanos , Masculino , Camundongos , Família Multigênica , Gradação de Tumores , Metástase Neoplásica , Neoplasias da Próstata/metabolismo , Interferência de RNA
10.
Clin Cancer Res ; 20(17): 4636-46, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24963047

RESUMO

PURPOSE: miR-409-3p/-5p is a miRNA expressed by embryonic stem cells, and its role in cancer biology and metastasis is unknown. Our pilot studies demonstrated elevated miR-409-3p/-5p expression in human prostate cancer bone metastatic cell lines; therefore, we defined the biologic impact of manipulation of miR-409-3p/-5p on prostate cancer progression and correlated the levels of its expression with clinical human prostate cancer bone metastatic specimens. EXPERIMENTAL DESIGN: miRNA profiling of a prostate cancer bone metastatic epithelial-to-mesenchymal transition (EMT) cell line model was performed. A Gleason score human tissue array was probed for validation of specific miRNAs. In addition, genetic manipulation of miR-409-3p/-5p was performed to determine its role in tumor growth, EMT, and bone metastasis in mouse models. RESULTS: Elevated expression of miR-409-3p/-5p was observed in bone metastatic prostate cancer cell lines and human prostate cancer tissues with higher Gleason scores. Elevated miR-409-3p expression levels correlated with progression-free survival of patients with prostate cancer. Orthotopic delivery of miR-409-3p/-5p in the murine prostate gland induced tumors where the tumors expressed EMT and stemness markers. Intracardiac inoculation (to mimic systemic dissemination) of miR-409-5p inhibitor-treated bone metastatic ARCaPM prostate cancer cells in mice led to decreased bone metastasis and increased survival compared with control vehicle-treated cells. CONCLUSION: miR-409-3p/-5p plays an important role in prostate cancer biology by facilitating tumor growth, EMT, and bone metastasis. This finding bears particular translational importance as miR-409-3p/-5p appears to be an attractive biomarker and/or possibly a therapeutic target to treat bone metastatic prostate cancer.


Assuntos
Neoplasias Ósseas/genética , Carcinogênese/genética , Transição Epitelial-Mesenquimal/genética , MicroRNAs/biossíntese , Animais , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , MicroRNAs/genética , Neoplasias da Próstata
11.
PLoS One ; 8(7): e68366, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874600

RESUMO

BACKGROUND: Bone metastasis is the most lethal form of several cancers. The ß2-microglobulin (ß2-M)/hemochromatosis (HFE) complex plays an important role in cancer development and bone metastasis. We demonstrated previously that overexpression of ß2-M in prostate, breast, lung and renal cancer leads to increased bone metastasis in mouse models. Therefore, we hypothesized that ß2-M is a rational target to treat prostate cancer bone metastasis. RESULTS: In this study, we demonstrate the role of ß2-M and its binding partner, HFE, in modulating radiation sensitivity and chemo-sensitivity of prostate cancer. By genetic deletion of ß2-M or HFE or using an anti-ß2-M antibody (Ab), we demonstrate that prostate cancer cells are sensitive to radiation in vitro and in vivo. Inhibition of ß2-M or HFE sensitized prostate cancer cells to radiation by increasing iron and reactive oxygen species and decreasing DNA repair and stress response proteins. Using xenograft mouse model, we demonstrate that anti-ß2-M Ab sensitizes prostate cancer cells to radiation treatment. Additionally, anti-ß2-M Ab was able to prevent tumor growth in an immunocompetent spontaneous prostate cancer mouse model. Since bone metastasis is lethal, we used a bone xenograft model to test the ability of anti-ß2-M Ab and radiation to block tumor growth in the bone. Combination treatment significantly prevented tumor growth in the bone xenograft model by inhibiting ß2-M and inducing iron overload. In addition to radiation sensitive effects, inhibition of ß2-M sensitized prostate cancer cells to chemotherapeutic agents. CONCLUSION: Since prostate cancer bone metastatic patients have high ß2-M in the tumor tissue and in the secreted form, targeting ß2-M with anti-ß2-M Ab is a promising therapeutic agent. Additionally, inhibition of ß2-M sensitizes cancer cells to clinically used therapies such as radiation by inducing iron overload and decreasing DNA repair enzymes.


Assuntos
Anticorpos/farmacologia , Sobrecarga de Ferro/induzido quimicamente , Proteínas de Membrana/antagonistas & inibidores , Neoplasias da Próstata/terapia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Microglobulina beta-2/antagonistas & inibidores , Animais , Anticorpos/uso terapêutico , Terapia Combinada , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Masculino , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/imunologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Tolerância a Radiação/genética , Radiossensibilizantes/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Microglobulina beta-2/imunologia , Microglobulina beta-2/metabolismo
12.
Transl Androl Urol ; 1(1): 19-32, 2012 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-22773967

RESUMO

We summarize several recent laboratory advances to tackle the problem of tumor-stroma-immune cell microenvironment interaction with the hope of developing and advancing new concepts and therapeutic strategies for prostate cancer therapy by improving bone and soft tissue metastases in prostate cancer patients. Given the emerging enthusiasm for immunotherapy in prostate cancer due to (I) improved understanding of the role of immune cells in the tumor microenvironment, (II) approval by the FDA of an immunotherapeutic drug to treat prostate cancer, and (III) recognition of immunotherapy as a novel approach to treat solid tumors by the Nobel Prize Committee (for discovery of dendritic cells that are used in immunotherapy), the field of tumor immunology is poised for growth in the next decade with the hope of developing new immunomodulatory drugs which will compliment and perhaps eventually replace traditional chemotherapeutic drugs. In this article, we provide a timely review of recent advances in the field of immunotherapy for prostate cancer, lessons learned from successes and failures, the contributory factors in the tumor microenvironment that could be rendered hostile to cancer cells, an exciting area of future research.

13.
Cancer Res ; 71(7): 2600-10, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21427356

RESUMO

Bone metastasis is one of the predominant causes of cancer lethality. This study demonstrates for the first time how ß2-microglobulin (ß2-M) supports lethal metastasis in vivo in human prostate, breast, lung, and renal cancer cells. ß2-M mediates this process by activating epithelial to mesenchymal transition (EMT) to promote lethal bone and soft tissue metastases in host mice. ß2-M interacts with its receptor, hemochromatosis (HFE) protein, to modulate iron responsive pathways in cancer cells. Inhibition of either ß2-M or HFE results in reversion of EMT. These results demonstrate the role of ß2-M in cancer metastasis and lethality. Thus, ß2-M and its downstream signaling pathways are promising prognostic markers of cancer metastases and novel therapeutic targets for cancer therapy.


Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias/metabolismo , Neoplasias/patologia , Microglobulina beta-2/metabolismo , Animais , Neoplasias Ósseas/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Técnicas de Silenciamento de Genes , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Hospedeiro Imunocomprometido , Imuno-Histoquímica , Ferro/metabolismo , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Neoplasias/imunologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transplante Heterólogo , Microglobulina beta-2/antagonistas & inibidores , Microglobulina beta-2/biossíntese , Microglobulina beta-2/imunologia
14.
Prostate ; 71(3): 232-40, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20672324

RESUMO

INTRODUCTION: Recent studies demonstrated the importance of ADAM9 in prostate cancer relapse upon therapy. In this study, we determined the role of ADAM9 in the therapeutic resistance to radiation and chemotherapy. MATERIALS AND METHODS: ADAM9 was either transiently or stably knocked down in C4-2 prostate cancer cells. The sensitivity of ADAM9 knockdown cells toward radiation and chemotherapeutic agents were determined. Additionally, the effects of ADAM9 knockdown on prostate cancer cell morphology, biochemical and functional alterations were accessed. RESULTS: Both transient and stable knockdown of ADAM9 resulted in increased apoptosis and increased sensitivity to radiation. ADAM9 knockdown also increased prostate cancer sensitivity to several chemotherapeutic drugs. ADAM9 knockdown resulted in increased E-cadherin and altered integrin expression and underwent phenotypic epithelial transition. These were reflected by the morphological, biochemical, and functional alterations in the ADAM9 knockdown cells. CONCLUSIONS: ADAM9 plays a crucial role in prostate cancer progression and therapeutic resistance in part by altering E-cadherin and integrin expression. ADAM9 is an important target for the consideration of treating prostate cancer patients who developed therapeutic resistance and disease relapse.


Assuntos
Proteínas ADAM/fisiologia , Epitélio/patologia , Proteínas de Membrana/fisiologia , Neoplasias da Próstata/terapia , Proteínas ADAM/análise , Proteínas ADAM/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Caderinas/análise , Linhagem Celular Tumoral , Humanos , Integrinas/análise , Masculino , Proteínas de Membrana/análise , Proteínas de Membrana/antagonistas & inibidores , Fenótipo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Tolerância a Radiação , Superóxidos/análise
15.
J Oncol ; 20102010.
Artigo em Inglês | MEDLINE | ID: mdl-20798867

RESUMO

HS-27a human bone stromal cells, in 2D or 3D coultures, induced cellular plasticity in human prostate cancer ARCaP(E) and ARCaP(M) cells in an EMT model. Cocultured ARCaP(E) or ARCaP(M) cells with HS-27a, developed increased colony forming capacity and growth advantage, with ARCaP(E) exhibiting the most significant increases in presence of bone or prostate stroma cells. Prostate (Pt-N or Pt-C) or bone (HS-27a) stromal cells induced significant resistance to radiation treatment in ARCaP(E) cells compared to ARCaP(M) cells. However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in both ARCaP(E)- and ARCaP(M)-cocultured cells. Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin. These cell adhesion molecules such as E-cadherin and integrin alpha v in cancer cells induce cell survival signals and mediate resistance to cancer treatments such as radiation.

16.
Int Immunol ; 22(7): 583-92, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20497960

RESUMO

MicroRNAs 125a and 125b are predicted to be able to bind to the B lymphocyte-induced maturation protein-1 (BLIMP-1) and IFN regulatory protein-4 (IRF-4) transcription factors, which are essential for plasma cell differentiation. A computational survey of the human and mouse genomes revealed that miR-125a and miR-125b are members of a multigene family located in paralogous clusters. The miR-125a cluster on chromosome 19 in humans includes miR-99b and let-7e, whereas the miR-125b cluster on chromosome 21 includes miR-99a and miR-let-7c. Our analysis of the expression profiles for these six miRs during B lineage differentiation indicated that mature miR-125a, miR-125b, miR-99b and let-7e transcripts are preferentially expressed by the actively dividing centroblasts in germinal centers (GC). However, miR-99b and let-7e are not predicted to bind BLIMP-1 or IRF-4 transcripts, and binding to the untranslated region of BLIMP-1 and IRF-4 messenger RNAs could be confirmed only for miR-125b. When the effect of miR-125b over-expression on terminal B cell differentiation was evaluated in an LPS-responsive B cell line, the induction of BLIMP-1 expression and IgM secretion was inhibited in this model system. Furthermore, miR-125b over-expression inhibited the differentiation of primary B cells and compromised the survival of cultured myeloma cells. These findings suggest that miR-125b promotes B lymphocyte diversification in GC by inhibiting premature utilization of essential transcription factors for plasma cell differentiation.


Assuntos
Linfócitos B/citologia , Diferenciação Celular , Centro Germinativo/citologia , MicroRNAs/genética , Animais , Linfócitos B/imunologia , Sequência de Bases , Linhagem Celular , Análise por Conglomerados , Sequência Conservada , Centro Germinativo/imunologia , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Camundongos , Modelos Animais , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Genética/genética
17.
J Immunol ; 181(7): 4590-602, 2008 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-18802061

RESUMO

Egr-1 (early growth response gene-1) is an immediate early gene encoding a zinc finger motif-containing transcription factor. Upon cross-linking of BCR, mature B cells undergo proliferation with an increase in Egr-1 message. Immature B lymphoma cells that express Egr-1 message and protein constitutively are growth inhibited when Egr-1 is down-regulated by negative signals from BCR or by antisense oligonucleotides. To test the hypothesis that Egr-1 is important for B cell development, we examined B cells from primary and secondary lymphoid organs in Egr-1(-/-) mice. Marginal zone B cell development was arrested in these mice, whereas the B cells in all other compartments were increased. To test the hypothesis that Egr-1 function may be partially compensated by other Egr family members, we developed transgenic mice expressing a dominant negative form of Egr-1, which lacks the trans activation domain but retains the DNA-binding domain, in a B cell-specific manner. There was a decrease in B lymphopoiesis in the bone marrow accompanied by a reduction in splenic immature and mature B cells as well as marginal zone B cells in the transgenic mice. Moreover, transgenic mice respond poorly to BCR cross-linking in vitro and T-independent and T-dependent Ags in vivo.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Proliferação de Células , Proteína 1 de Resposta de Crescimento Precoce/genética , Animais , Antígenos T-Independentes/fisiologia , Linfócitos B/citologia , Diferenciação Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Proteína 1 de Resposta de Crescimento Precoce/deficiência , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Feminino , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Linfopoese/genética , Linfopoese/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos B/fisiologia
18.
PLoS One ; 2(9): e863, 2007 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-17848994

RESUMO

BACKGROUND: Toll-like receptors (TLRs) are pattern recognition receptors that recognize pathogen associated molecular patterns and trigger innate immunity leading to initiation of adaptive immunity. TLR-mediated activation of dendritic cells (DCs) is known to be a critical event in the initiation of cellular and humoral immune responses. Recent work however suggests that B cells also express TLRs, and that they can be activated via TLR ligands. However, whether such B cell activation occurs only on memory B cells, or whether it can also occur on truly naïve B cells remains controversial. Furthermore, the expression and functional relevance of TLRs on distinct subsets of B cells, which are known to play differential roles in humoral responses is not known. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the expression pattern of different TLRs in distinct subsets of murine B cells (naïve, memory, follicular, marginal zone, B-1 and peyer's patch). In contrast to the reported restricted expression pattern of TLRs in human peripheral blood naïve B cells, murine splenic naïve B cells express a variety of TLRs with the exception of TLR5 and 8. Consistent with this relatively broad expression pattern, murine naive B cells proliferate and secrete antibody to a variety of TLR agonists in vitro, in the absence of B-cell receptor cross-linking. In addition, we observed subtle differences in the antibody secretion pattern of follicular, marginal zone, B-1 and peyer's patch B-cell subsets. CONCLUSIONS/SIGNIFICANCE: Thus various B cell subsets, including truly naïve B cells, express multiple TLRs, and signaling via such TLRs results in their robust proliferation and antibody secretion, even in the absence of dendritic cell activation, or T-cell help.


Assuntos
Linfócitos B/imunologia , Membrana Mucosa/imunologia , Baço/imunologia , Receptores Toll-Like/genética , Animais , Subpopulações de Linfócitos B , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Perfilação da Expressão Gênica , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/citologia , Membrana Mucosa/metabolismo , Reação em Cadeia da Polimerase , Baço/citologia , Baço/metabolismo
19.
J Immunol ; 178(1): 111-21, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17182546

RESUMO

Curcumin (diferuloylmethane), a component of dietary spice turmeric (Curcuma longa), has been shown in recent studies to have therapeutic potential in the treatment of cancer, diabetes, arthritis, and osteoporosis. We investigated the ability of curcumin to modulate the growth of B lymphomas. Curcumin inhibited the growth of both murine and human B lymphoma in vitro and murine B lymphoma in vivo. We also demonstrate that curcumin-mediated growth inhibition of B lymphoma is through inhibition of the survival kinase Akt and its key target Bad. However, in vitro kinase assays show that Akt is not a direct target of curcumin. We identified a novel target for curcumin in B lymphoma viz spleen tyrosine kinase (Syk). Syk is constitutively activated in primary tumors and B lymphoma cell lines and curcumin down-modulates Syk activity accompanied by down-regulation of Akt activation. Moreover, we show that overexpression of Akt, a target of Syk, or Bcl-x(L), a target of Akt can overcome curcumin-induced apoptosis of B lymphoma cells. These observations suggest a novel growth promoting role for Syk in lymphoma cells.


Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Linfoma de Células B/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Apoptose , Antígenos CD79/metabolismo , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Linfoma de Células B/patologia , Camundongos , Camundongos Endogâmicos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos B , Especificidade por Substrato , Quinase Syk , Células Tumorais Cultivadas , Proteína de Morte Celular Associada a bcl/metabolismo , Proteína bcl-X/metabolismo
20.
J Biol Chem ; 281(52): 39806-18, 2006 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-17065146

RESUMO

Cross-linking of the B cell receptor (BCR) on the immature B lymphoma cell line BKS-2 induces growth inhibition and apoptosis accompanied by rapid down-regulation of the immediate-early gene egr-1. In these lymphoma cells, egr-1 is expressed constitutively and has a prosurvival role, as Egr-1-specific antisense oligonucleotides or expression of a dominant-negative inhibitor of Egr-1 also prevented the growth of BKS-2 cells. Moreover, enhancement of Egr-1 protein with phorbol 12-myristate 13-acetate or an egr-1 expression vector rescued BKS-2 cells from BCR signal-induced growth inhibition. Nuclear run-on and mRNA stability assays indicated that BCR-derived signals act at the transcriptional level to reduce egr-1 expression. Inhibitors of ERK and JNK (but not of p38 MAPK) reduced egr-1 expression at the protein level. Transcriptional regulation appears to have a role because egr-1 promoter-driven luciferase expression was reduced by ERK and JNK inhibitors. Promoter truncation experiments suggested that several serum response elements are required for MAPK-mediated egr-1 expression. Our study suggests that BCR signals reduce egr-1 expression by inhibiting activation of ERK and JNK. Unlike ERK and JNK, p38 MAPK reduces constitutive expression of egr-1. Unlike the immature B lymphoma cells, normal immature B cells did not exhibit constitutive MAPK activation. BCR-induced MAPK activation was modest and transient with a small increase in egr-1 expression in normal immature B cells consistent with their inability to proliferate in response to BCR cross-linking.


Assuntos
Diferenciação Celular/fisiologia , Regulação para Baixo/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Linfoma de Células B/enzimologia , Receptores de Antígenos de Linfócitos B/fisiologia , Animais , Linhagem Celular Tumoral , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Feminino , Inibidores do Crescimento/farmacologia , Inibidores do Crescimento/fisiologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Oligonucleotídeos Antissenso/farmacologia , Retroviridae/fisiologia , Proteínas WT1/biossíntese , Proteínas WT1/genética , Proteínas WT1/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
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