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1.
Cancer Sci ; 111(3): 807-816, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31908105

RESUMO

Activation-induced cell death (AICD) mediated by the Fas/Fas ligand (FasL) system plays a key role in regulating immune response. Although normal natural killer (NK) cells use this system for their homeostasis, malignant NK cells seem to disrupt the process. Extranodal NK/T-cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL-derived NK cell lines NK-YS and Hank1, and primary lymphoma cells expressed procaspase-8/FADD-like interleukin-1ß-converting enzyme (FLICE) modulator and cellular FLICE-inhibitory protein (c-FLIP), along with Fas and FasL. Compared with Fas-sensitive Jurkat cells, NK-YS and Hank1 showed resistance to Fas-mediated apoptosis in spite of the same expression levels of c-FLIP and the death-inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c-FLIP (c-FLIPL ) was coimmunoprecipitated with Fas predominantly in both ENKL-derived NK cell lines after Fas ligation. Indeed, c-FLIPL was more sufficiently recruited to the DISC in both ENKL-derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c-FLIPL per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK-YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c-FLIPL , which prevents their Fas-mediated apoptosis. Our results show that c-FLIPL could be a promising therapeutic target against ENKL.


Assuntos
Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Células Matadoras Naturais/metabolismo , Linfoma/metabolismo , Receptor fas/metabolismo , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 8/metabolismo , Caspases/metabolismo , Morte Celular/fisiologia , Proteína Ligante Fas , Proteína de Domínio de Morte Associada a Fas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Jurkat , Isoformas de Proteínas/metabolismo , Transdução de Sinais/fisiologia
2.
Immunol Rev ; 291(1): 190-213, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402495

RESUMO

Signals emanating from the B-cell receptor (BCR) promote proliferation and survival in diverse forms of B-cell lymphoma. Precision medicine strategies targeting the BCR pathway have been generally effective in treating lymphoma, but often fail to produce durable responses in diffuse large B-cell lymphoma (DLBCL), a common and aggressive cancer. New insights into DLBCL biology garnered from genomic analyses and functional proteogenomic studies have identified novel modes of BCR signaling in this disease. Herein, we describe the distinct roles of antigen-dependent and antigen-independent BCR signaling in different subtypes of DLBCL. We highlight mechanisms by which the BCR cooperates with TLR9 and mutant isoforms of MYD88 to drive sustained NF-κB activity in the activated B-cell-like (ABC) subtype of DLBCL. Finally, we discuss progress in detecting and targeting oncogenic BCR signaling to improve the survival of patients with lymphoma.


Assuntos
Leucemia Linfoide/etiologia , Leucemia Linfoide/metabolismo , Linfoma/etiologia , Linfoma/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Animais , Autoantígenos/imunologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/terapia , Linfoma/diagnóstico , Linfoma/terapia , Receptores de Antígenos de Linfócitos B/genética
3.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31405039

RESUMO

SUMO (Small Ubiquitin-related MOdifier) is a post-translational modifier of the ubiquitin family controlling the function and fate of thousands of proteins. SUMOylation is deregulated in various hematological malignancies, where it participates in both tumorigenesis and cancer cell response to therapies. This is the case for Acute Promyelocytic Leukemias (APL) where SUMOylation, and subsequent destruction, of the PML-RARα fusion oncoprotein are triggered by arsenic trioxide, which is used as front-line therapy in combination with retinoic acid to cure APL patients. A similar arsenic-induced SUMO-dependent degradation was also documented for Tax, a human T-cell lymphotropic virus type I (HTLV1) viral protein implicated in Adult T-cell Leukemogenesis. SUMOylation also participates in Acute Myeloid Leukemia (AML) response to both chemo- and differentiation therapies, in particular through its ability to regulate gene expression. In Multiple Myeloma, many enzymes of the SUMO pathway are overexpressed and their high expression correlates with lower response to melphalan-based chemotherapies. B-cell lymphomas overexpressing the c-Myc oncogene also overexpress most components of the SUMO pathway and are highly sensitive to SUMOylation inhibition. Targeting the SUMO pathway with recently discovered pharmacological inhibitors, alone or in combination with current therapies, might therefore constitute a powerful strategy to improve the treatment of these cancers.


Assuntos
Leucemia/metabolismo , Linfoma/metabolismo , Mieloma Múltiplo/metabolismo , Proteína SUMO-1/metabolismo , Animais , Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/metabolismo , Humanos , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sumoilação/efeitos dos fármacos
4.
Pol J Vet Sci ; 22(2): 203-211, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31269334

RESUMO

Matrix metalloproteinases 2 and 9 (MMP2 and MMP9) are proteolytic enzymes involved with extracellular matrix degradation. They play a role in tumor invasion and metastases. Because of their ability to degrade signaling molecules presented in extracellular matrix, MMPs contribute to tumor proliferation and apoptosis. The aim of this study was to evaluate expression of MMP2 (latent and both active and latent forms) and MMP9 (active, latent, active and latent forms) in different subtypes of canine lymphomas and their relationship with proliferative (mitotic index and percentage of Ki67-positive cells) and apoptotic (apoptotic index) markers. Expression of MMPs was assessed immunohistochemically using an immunoreactive score system. Expression of both MMPs was found in all 20 examined lymphomas belonging to six subtypes. Most cases showed a moderate level of all analyzed forms of MMP2 and MMP9. High expression of MMPs was found in single cases. Except for a positive correlation between the active form of MMP9 and the mitotic index for all lymphoma cases, no other correlations between any remaining forms of MMPs and neither proliferative nor apoptotic markers were found, irrespective of whether the analysis encompassed all cases or the most numerous lymphoma subtypes i.e. centroblastic and Burkitt-like. Our results were not able to clearly confirm the influence of MMPs on the proliferation and apoptotic activity of canine lymphoma cells. However, further studies examining MMPs activity by zymography, expression of their inhibitors and other factors involved in activation of cell proliferation and apoptosis inhibition are needed to clarify the role of MMPs, especially the active form of MMP9, in the behavior of canine lymphoma cells.


Assuntos
Proliferação de Células/fisiologia , Doenças do Cão/metabolismo , Regulação Neoplásica da Expressão Gênica , Linfoma/veterinária , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Animais , Anticorpos , Antígenos , Apoptose/fisiologia , Biomarcadores Tumorais , Cães , Regulação Enzimológica da Expressão Gênica , Imuno-Histoquímica/veterinária , Linfoma/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética
5.
Oncol Rep ; 42(3): 1248-1256, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322273

RESUMO

Ribavirin exhibits inhibitory effects on the epigenetic enzyme enhancer of zeste homolog 2 (EZH2), which participates in lymphomagenesis. Additionally, preclinical and clinical studies have demonstrated the anti­lymphoma activity of this drug. To further investigate the potential of ribavirin as an anticancer treatment for lymphoma, the tumor­suppressive effects of ribavirin were analyzed in lymphoma cell lines. The effects of ribavirin on the viability and clonogenicity of the B­cell lymphoma cell line Pfeiffer (EZH2­mutant), Toledo (EZH2 wild­type) and cutaneous T­cell lymphoma Hut78 cell line were assessed. Expression of EZH2 and trimethylation status of histone 3, lysine 27 trimethylated (H3K27m3) was also determined in response to ribavirin. The transcriptional effects of ribavirin on Hut78 cells were analyzed by microarray expression and the results were validated by reverse transcription­quantitative polymerase chain reaction, western blotting and knockout of signal transducer and activator of transcription 1 (STAT1). The results of the present study demonstrated that ribavirin suppressed the growth and clonogenicity of cells in a dose­dependent manner. Ribavirin did not affect the expression of EZH2 nor altered its activity as evaluated by H3K27 trimethylation status. Furthermore, the results of transcriptome analysis indicated that the majority of the canonical pathways affected by ribavirin were associated with the immune system, including 'antigen presentation', 'communication between innate and adaptive immune cells' and 'cross­talk between dendritic and natural killer cells'. The results of gene expression analysis were confirmed, by demonstrating at the RNA and protein levels, downregulation of stearoyl­CoA desaturase and upregulation of STAT1. Depletion of STAT1, which was proposed as a key regulator of the aforementioned pathways, exerted growth inhibitory effects almost to the same extent as ribavirin. In conclusion, ribavirin was proposed to exert growth inhibitory effects on lymphoma cell lines, particularly Hut78 cells, a cutaneous T­cell lymphoma cell line. Of note, these effects may depend on, at least in part, the activation of canonical immune pathways regulated by the key factors STAT1 and interferon­Î³. Our results provide insight into the anti­lymphoma potential of ribavirin; however, further investigations in preclinical and clinical studies are required to determine the effectiveness of ribavirin as a therapeutic agent for treating lymphoma.


Assuntos
Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linfoma/patologia , Ribavirina/farmacologia , Biomarcadores Tumorais/metabolismo , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigenômica , Perfilação da Expressão Gênica , Humanos , Linfoma/tratamento farmacológico , Linfoma/genética , Linfoma/metabolismo , Células Tumorais Cultivadas
6.
EMBO J ; 38(14): e101564, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304633

RESUMO

DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog HDAC1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of Hdac1 retained the increased H3K79 methylation and were sensitive to reduced DOT1L dosage. Furthermore, cell lines derived from Hdac1Δ/Δ thymic lymphomas were sensitive to a DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development.


Assuntos
Histona Desacetilase 1/genética , Histona Desacetilase 2/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Linfoma/metabolismo , Neoplasias do Timo/metabolismo , Acetilação , Animais , Linhagem Celular Tumoral , Deleção de Genes , Histona Desacetilases/genética , Humanos , Linfoma/genética , Metilação , Camundongos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Neoplasias do Timo/genética
7.
Molecules ; 24(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31248049

RESUMO

Lymphoma defines a group of different diseases. This study examined pre-treatment plasma samples from 66 adult patients (aged 20-74) newly diagnosed with any lymphoma subtype, and 96 frequency matched population controls. We used gas chromatography-mass spectrometry (GC-MS) to compare the metabolic profile by case/control status and across the major lymphoma subtypes. We conducted univariate and multivariate analyses, and partial least square discriminant analysis (PLS-DA). When compared to the controls, statistically validated models were obtained for diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and Hodgkin lymphoma (HL), but not follicular lymphoma (FL). The metabolomic analysis highlighted interesting differences between lymphoma patients and population controls, allowing the discrimination between pathologic and healthy subjects: Important metabolites, such as hypoxanthine and elaidic acid, were more abundant in all lymphoma subtypes. The small sample size of the individual lymphoma subtypes prevented obtaining PLS-DA validated models, although specific peculiar features of each subtype were observed; for instance, fatty acids were most represented in MM and HL patients, while 2-aminoadipic acid, 2-aminoheptanedioic acid, erythritol, and threitol characterized DLBCL and CLL. Metabolomic analysis was able to highlight interesting differences between lymphoma patients and population controls, allowing the discrimination between pathologic and healthy subjects. Further studies are warranted to understand whether the peculiar metabolic patterns observed might serve as early biomarkers of lymphoma.


Assuntos
Linfoma/metabolismo , Metaboloma , Metabolômica , Idoso , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Linfoma/diagnóstico , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Projetos Piloto
8.
Crit Rev Oncol Hematol ; 141: 73-81, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31252322

RESUMO

This study aimed to assess the false-positive proportion of follow-up 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in lymphoma patients who initially achieved an end-of-treatment complete remission, using biopsy as reference standard. Medline was searched for original studies, studies were methodologically evaluated and results were meta-analytically summarized. Proportion of false-positive results ranged between 9.5%-90.0%, with a weighted summary proportion (random effects) of 42.9% (95% confidence interval [CI]: 29.0%-58.0%). A separate subgroup analysis in symptomatic patients only again revealed a relatively high summary proportion of false-positive follow-up FDG-PET of 37.5% (random effects). In conclusion, the false-positive proportion of follow-up FDG-PET in lymphoma patients who initially achieved an end-of-treatment complete remission is high and remains high when a combination of clinical symptoms and follow-up FDG-PET is used. Therefore, biopsy remains compulsory and follow-up FDG-PET alone may be regarded as unreliable to define progression-free survival.


Assuntos
Fluordesoxiglucose F18 , Linfoma/diagnóstico , Monitorização Fisiológica , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Pré-Escolar , Reações Falso-Positivas , Feminino , Fluordesoxiglucose F18/farmacocinética , Seguimentos , Humanos , Linfoma/epidemiologia , Linfoma/metabolismo , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Monitorização Fisiológica/estatística & dados numéricos , Tomografia por Emissão de Pósitrons/normas , Indução de Remissão , Adulto Jovem
10.
Biol Pharm Bull ; 42(6): 937-943, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155590

RESUMO

Hydroxyoctadecadienoic acids (HODEs) are generated by oxidation of linoleic acid in vivo and thought to mediate various pathophysiological responses. In this study, we examined the effects of HODEs on EL4 mouse lymphoma cell growth and found that 9-(E,Z)-HODE inhibited EL4 cell growth in a dose-dependent manner, whereas no such growth inhibition was observed with other isomers (9-(E,E)-, 13-(Z,E)-, or 13-(E,E)-HODE), suggesting that the growth-inhibitory effect of HODEs was stereospecific. Analysis by flow cytometry (FACS) with annexin V and propidium iodide (PI) staining showed that 9-(E,Z)-HODE induced apoptosis with G2/M phase arrest. We next examined the growth inhibition profile of 9-(E,Z)-HODE against a panel of 39 human cancer cell lines (JFCR39). The fingerprint of growth inhibition by 9-(E,Z)-HODE exhibited a high degree of similarity to that by MLN4924, an inhibitor of NEDD8-activating enzyme. The intracellular NEDD8 (ubiquitin-like protein) expression in EL4 cells was decreased by the treatment with 9-(E,Z)-HODE as assessed by immunoblotting and flow cytometry. In conclusion, 9-(E,Z)-HODE specifically induced G2/M phase arrest and apoptosis, and the decrease of NEDD8 expression might be involved in this effect.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ácidos Graxos Insaturados/farmacologia , Linfoma/metabolismo , Animais , Linhagem Celular Tumoral , Ácidos Graxos Insaturados/química , Linfoma/patologia , Camundongos , Proteína NEDD8/metabolismo , Estereoisomerismo
12.
BMC Biotechnol ; 19(1): 28, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118070

RESUMO

BACKGROUND: In vivo use of monoclonal antibodies has become routine clinical practice in the treatment of human cancer. CD38 is an attractive target, because it has double roles, as a receptor and an ectoenzyme. Daratumumab, an anti-CD38 antibody, is currently in the clinical trials for multiple myeloma. RESULTS: Here we obtained a humanized anti-CD38 antibody, SG003, using SDR-grafting method. SG003 possessed stronger antigen binding activity than Daratumumab, and its epitope was far from that of Daratumumab, an anti-CD38 antibody currently in the clinical trials for multiple myeloma; besides, SG003 showed enhanced antibody-dependent cell-mediated cytotoxicity function and in vivo inhibitory efficacy of tumor growth in xenograft mice model. CONCLUSION: SG003 seemed to be a good option to improve the curative effect of CD38-related cancers.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , Anticorpos Monoclonais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Linfoma/tratamento farmacológico , ADP-Ribosil Ciclase 1/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linhagem Celular Tumoral , Epitopos/imunologia , Epitopos/metabolismo , Humanos , Linfoma/imunologia , Linfoma/metabolismo , Camundongos SCID , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Clin Nucl Med ; 44(10): e590-e592, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31058689

RESUMO

Tc-TRODAT-1, as a tropane-derived compound with highly selective binding to the dopamine transporter, has been extensively used as an in vivo biomarker to evaluate parkinsonism. There have been few reports indicating various etiologies about extrastriatal findings on the Tc-TRODAT-1 SPECT. We herein present an interesting case about the incidental discovery of brain lymphoma with increasing uptake of Tc-TRODAT-1.


Assuntos
Encéfalo/diagnóstico por imagem , Linfoma/diagnóstico por imagem , Compostos de Organotecnécio , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos , Transporte Biológico , Encéfalo/metabolismo , Feminino , Humanos , Achados Incidentais , Linfoma/metabolismo , Pessoa de Meia-Idade , Compostos de Organotecnécio/metabolismo , Tropanos/metabolismo
14.
Am J Vet Res ; 80(6): 572-577, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31140843

RESUMO

OBJECTIVE: To investigate luteinizing hormone (LH) receptor expression in canine nonneoplastic and neoplastic lymph nodes, circulating nonneoplastic lymphocytes, and T-cell lymphoma (TCL) cell lines. SAMPLE: Formalin-fixed, paraffin-embedded lymph nodes (5 neoplastic and 3 nonneoplastic) from 6 dogs, circulating lymphocytes from venous blood specimens obtained from 12 healthy dogs, and 3 TCL cell lines derived from 3 dogs with primary lymphoma. PROCEDURES: Lymph node specimens were immunohistochemically stained for determination of LH receptor expression. Circulating nonneoplastic lymphocytes and TCL cell lines were evaluated for LH receptor expression by use of flow cytometry; circulating lymphocytes were also immunophenotyped. The mean percentage of cells positive for LH receptors was determined for each type of specimen. For the healthy dogs, percentages of circulating B and T lymphocytes that expressed LH receptors were assessed on the basis of sex and reproductive status. RESULTS: The mean percentage of LH receptor-positive cells in canine neoplastic and nonneoplastic lymph nodes was 12.4% and 4.1%, respectively. For the healthy dogs, the mean percentage of circulating LH receptor-positive T lymphocytes was significantly higher in gonadectomized dogs (16.6%) than in sexually intact dogs (10.5%); the percentages of circulating LH receptor-positive B lymphocytes did not significantly differ by reproductive status. Among the 3 canine TCL cell lines, LH receptor expression ranged from 10% to 45%. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, LH receptor expression by canine neoplastic and nonneoplastic lymphocytes was detected. Research into the effects of downregulation of LH receptor activation in dogs with lymphoma is warranted.


Assuntos
Doenças do Cão/metabolismo , Linfócitos/metabolismo , Linfoma/veterinária , Receptores do LH/biossíntese , Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Doenças do Cão/imunologia , Doenças do Cão/patologia , Cães , Feminino , Citometria de Fluxo/veterinária , Linfonodos/metabolismo , Linfoma/imunologia , Linfoma/metabolismo , Masculino
15.
Mol Cell Biochem ; 459(1-2): 49-59, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31098783

RESUMO

Glucocorticoid (GC) resistance is associated with poor response to the following chemotherapy in lymphoid malignancies, such as lymphoma and leukemia. However, it remains unclear whether GCs interfere with the cytotoxic effects of anti-cancer drugs on GC-resistant cells. In this study, we examined whether GCs affected the sensitivities to vincristine (VCR)/doxorubicin (DOX) and the expression of drug transporters in GC-resistant cells. The dexamethasone (DEX)/prednisolone (PSL)-resistant lymphoid and non-lymphoid cell lines Raji and HL60 were cultured with DEX for 7 days and then treated with VCR or DOX for 3 days. Seven days of DEX treatment increased the IC50s of both VCR and DOX in Raji cells but not in HL60 cells. The mRNA and protein expression levels of organic cation/carnitine transporter (OCTN) 2, one of the drug uptake transporters expressed in both cell lines, were decreased only in Raji cells. When Raji cells were cultured with PSL, the IC50 of DOX but not VCR increased as the expression of OCTN2 decreased. No significant increases in efflux transporter expression were induced by DEX or PSL. When siRNA against OCTN2 was introduced into Raji cells, the IC50 of DOX but not VCR increased significantly. These data suggested that both DEX and PSL decreased the sensitivity of the DEX/PSL-resistant Raji cells to DOX, a change that was at least partially due to reductions in OCTN2. Thus, the continuous usage of GCs may interfere with the effects of chemotherapy on GC-resistant lymphoid cells.


Assuntos
Dexametasona/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucocorticoides/farmacologia , Linfócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Prednisolona/farmacologia , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Células HL-60 , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Linfócitos/patologia , Linfoma/tratamento farmacológico , Linfoma/metabolismo , Linfoma/patologia
16.
J Zhejiang Univ Sci B ; 20(5): 391-398, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31090265

RESUMO

Sirtuin 1 (SIRT1) is a protein deacetylase, which regulates various physiological activities by deacetylating different protein substrates. An increasing number of studies have revealed critical roles of SIRT1 in different aspects of cancers including metabolism, proliferation, genomic instability, and chemotherapy resistance. Depending on the protein targets in a certain oncogenic context, SIRT1 may play a unique role in each individual blood cancer subtype. Our previous work showed that activation of SIRT1 in primitive leukemia cells of acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) promotes disease maintenance. On the other hand, an SIRT1 agonist was shown to disrupt maintenance of myelodysplastic syndrome (MDS) stem cells and holds promise as a potential therapeutic approach. Herein, we present a concise summary of the different functions of SIRT1 in hematologic malignancies.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Hematológicas/metabolismo , Sirtuína 1/metabolismo , Proliferação de Células , Sobrevivência Celular , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/metabolismo , Linfoma/metabolismo , Síndromes Mielodisplásicas/metabolismo , Fenótipo , Microambiente Tumoral
17.
Dermatol Online J ; 25(2)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30865410

RESUMO

A blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a cutaneous lymphoma derived from a plasmacytoid dendritic precursor cell that exhibits aggressive clinical behavior. Herein, we report a 46-year-old woman with a complaint of a painless nodule on the back, associated with pruritus. The nodule grew and new growths appeared over six months of evolution. The histopathological examination of one of the left upper limb lesions showed a dense lymphoid cell infiltrate with atypia in the superficial and deep dermis. Immunohistochemistry showed positivity for CD45, S-100 protein, CD123, and TCL 1. About two months after the initial evaluation, the patient was admitted to the Emergency Hospital of Marituba-PA with dyspnea. She progressed to cardiorespiratory arrest and death within 12 hours of admission. There is still no consensus for the treatment of BPDCN. Intensive therapy for acute leukemia can be useful, but allogeneic bone marrow transplantation has a greater chance of long-term survival.


Assuntos
Células Dendríticas/patologia , Linfoma/patologia , Neoplasias Cutâneas/patologia , Antígenos CD4/metabolismo , Evolução Fatal , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Linfoma/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/metabolismo , Proteínas S100/metabolismo , Neoplasias Cutâneas/metabolismo
18.
J Biol Chem ; 294(19): 7692-7710, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-30885941

RESUMO

Epigenetic regulation by the type II protein arginine methyltransferase, PRMT5, plays an essential role in the control of cancer cell proliferation and tumorigenesis. In this report, we investigate the relationship between PRMT5 and WNT/ß-CATENIN as well as AKT/GSK3ß proliferative signaling in three different types of non-Hodgkin's lymphoma cell lines, clinical samples, and mouse primary lymphoma cells. We show that PRMT5 stimulates WNT/ß-CATENIN signaling through direct epigenetic silencing of pathway antagonists, AXIN2 and WIF1, and indirect activation of AKT/GSK3ß signaling. PRMT5 inhibition with either shRNA-mediated knockdown or a specific small molecule PRMT5 inhibitor, CMP-5, not only leads to derepression of WNT antagonists and decreased levels of active phospho-AKT (Thr-450 and Ser-473) and inactive phospho-GSK3ß (Ser-9) but also results in decreased transcription of WNT/ß-CATENIN target genes, CYCLIN D1, c-MYC, and SURVIVIN, and enhanced lymphoma cell death. Furthermore, PRMT5 inhibition leads to reduced recruitment of co-activators CBP, p300, and MLL1, as well as enhanced recruitment of co-repressors HDAC2 and LSD1 to the WNT/ß-CATENIN target gene promoters. These results indicate that PRMT5 governs expression of prosurvival genes by promoting WNT/ß-CATENIN and AKT/GSK3ß proliferative signaling and that its inhibition induces lymphoma cell death, which warrants further clinical evaluation.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Linfoma/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Via de Sinalização Wnt , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Glicogênio Sintase Quinase 3 beta/genética , Linfoma/genética , Linfoma/patologia , Camundongos , Proteína-Arginina N-Metiltransferases/genética , Proteínas Proto-Oncogênicas c-akt/genética , beta Catenina/genética , beta Catenina/metabolismo
19.
Diagn Cytopathol ; 47(7): 725-732, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30897306

RESUMO

Undifferentiated malignant SMARCA4-deficient neoplasms are rare, recently characterized, high grade, potentially lethal malignancies. Such tumors are characterized by the loss of BRG1 encoded by SMARCA4, a key component of the Switch/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling complex. As this complex, also referred as BAF (BRG1/BRM associated factors) complex, is involved in the epigenetic control of hundreds of genes, including those involved in lineage-specific differentiation, BAF-deficient tumors, show minimal or no differentiation and are difficult to classify. Their fine needle aspiration (FNA) cytologic features are still poorly defined. Here, we describe a 70-year-old man who presented with thickening of the wall of the distal esophagus and stomach and multiple liver and lung lesions. Liver FNA showed relatively uniform dispersed malignant cells with high nucleus: cytoplasm ratio, scant microvacuolated cytoplasm, eccentric nuclei and prominent nucleoli. Mitoses, necrotic debris, nuclear streak artifact, "ghost cells" and focal rhabdoid cytoplasmic inclusions were also present. The liver core biopsy and GI biopsies demonstrated sinusoidal and respectively submucosal involvement by a high grade undifferentiated malignant neoplasm. The tumor cells were negative for all applied markers on immunohistochemistry and flow cytometry, and only showed CD138 and weak PAX5 staining. After an initial diagnosis of hematolymphoid neoplasm, additional stains showed intact INI1 protein and loss of BRG1 protein immunoexpression, establishing the accurate diagnosis. This case highlights the difficulties and potential pitfalls encountered in the FNA diagnosis of BAF-deficient tumors, the accurate diagnosis of which is important due to their lack of response to conventional therapy and potential response to targeted therapy.


Assuntos
Carcinoma/patologia , DNA Helicases/metabolismo , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Linfoma/patologia , Proteínas Nucleares/metabolismo , Neoplasias Gástricas/patologia , Fatores de Transcrição/metabolismo , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , DNA Helicases/genética , Diagnóstico Diferencial , Neoplasias Esofágicas/metabolismo , Humanos , Linfoma/metabolismo , Masculino , Metástase Neoplásica , Proteínas Nucleares/genética , Fator de Transcrição PAX5/genética , Fator de Transcrição PAX5/metabolismo , Neoplasias Gástricas/metabolismo , Sindecana-1/genética , Sindecana-1/metabolismo , Fatores de Transcrição/genética
20.
Biomolecules ; 9(3)2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836703

RESUMO

The CDKN2a/ARF locus expresses two partially overlapping transcripts that encode two distinct proteins, namely p14ARF (p19Arf in mouse) and p16INK4a, which present no sequence identity. Initial data obtained in mice showed that both proteins are potent tumor suppressors. In line with a tumor-suppressive role, ARF-deficient mice develop lymphomas, sarcomas, and adenocarcinomas, with a median survival rate of one year of age. In humans, the importance of ARF inactivation in cancer is less clear whereas a more obvious role has been documented for p16INK4a. Indeed, many alterations in human tumors result in the elimination of the entire locus, while the majority of point mutations affect p16INK4a. Nevertheless, specific mutations of p14ARF have been described in different types of human cancers such as colorectal and gastric carcinomas, melanoma and glioblastoma. The activity of the tumor suppressor ARF has been shown to rely on both p53-dependent and independent functions. However, novel data collected in the last years has challenged the traditional and established role of this protein as a tumor suppressor. In particular, tumors retaining ARF expression evolve to metastatic and invasive phenotypes and in humans are associated with a poor prognosis. In this review, the recent evidence and the molecular mechanisms of a novel role played by ARF will be presented and discussed, both in pathological and physiological contexts.


Assuntos
Adenocarcinoma/metabolismo , Linfoma/metabolismo , Sarcoma/metabolismo , Proteína Supressora de Tumor p14ARF/química , Proteína Supressora de Tumor p14ARF/metabolismo , Adenocarcinoma/genética , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Linfoma/genética , Camundongos , Camundongos Knockout , Sarcoma/genética , Proteína Supressora de Tumor p14ARF/deficiência , Proteína Supressora de Tumor p14ARF/genética
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