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1.
J Cell Sci ; 135(5)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34080635

RESUMO

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21 (also known as ZDHHC21), a member of the DHHC family of mammalian protein acyltransferases, mediates T cell receptor-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice, which express a functionally deficient version of DHHC21, we show that DHHC21 is a Ca2+/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We find that disruption of the Ca2+/calmodulin-binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2 and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity.

2.
Front Immunol ; 9: 1884, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30158933

RESUMO

T follicular helper (Tfh) cells play key role in providing help to B cells during germinal center (GC) reactions. Generation of protective antibodies against various infections is an important aspect of Tfh-mediated immune responses and the dysregulation of Tfh cell responses has been implicated in various autoimmune disorders, inflammation, and malignancy. Thus, their differentiation and maintenance must be closely regulated to ensure appropriate help to B cells. The generation and function of Tfh cells is regulated by multiple checkpoints including their early priming stage in T zones and throughout the effector stage of differentiation in GCs. Signaling pathways activated downstream of cytokine and costimulatory receptors as well as consequent activation of subset-specific transcriptional factors are essential steps for Tfh cell generation. Thus, understanding the mechanisms underlying Tfh cell-mediated immunity and pathology will bring into spotlight potential targets for novel therapies. In this review, we discuss the recent findings related to the molecular mechanisms of Tfh cell differentiation and their role in normal immune responses and antibody-mediated diseases.


Assuntos
Suscetibilidade a Doenças , Imunidade Celular , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Autoimunidade , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citocinas/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Linfócitos T Auxiliares-Indutores/citologia
3.
Oncotarget ; 9(2): 2591-2602, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29416794

RESUMO

Maternal embryonic leucine zipper kinase (MELK) is known to modulate intracellular signaling and control cellular processes. However, the role of MELK in oncogenesis is not well defined. In this study, using two microarray datasets of neuroblastoma (NB) patients, we identified that MELK expression is significantly correlated to poor overall survival, unfavorable prognosis, and high-risk status. We found that MELK is a direct transcription target of MYCN and MYC in NB, and MYCN increases MELK expression via direct promoter binding. Interestingly, knockdown of MELK expression significantly reduced the phosphorylation of target protein Retinoblastoma (pRb) and inhibited NB cell growth. Furthermore, pharmacological inhibition of MELK activity by small-molecule inhibitor OTSSP167 significantly inhibited cell proliferation, anchorage-independent colony formation, blocked cell cycle progression, and induced apoptosis in different NB cell lines including a drug-resistant cell line. Additionally, OTSSP167 suppressed NB tumor growth in an orthotopic xenograft mouse model. Overall, our data suggest that MELK is a novel therapeutic target for NB and its inhibitor OTSSP167 is a promising drug for further clinical development.

4.
Int J Clin Exp Pathol ; 11(5): 2347-2355, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-31938346

RESUMO

Doxorubicin (DOX) is the most common chemotherapeutic drug for treatment of breast cancer but intrinsic and acquired resistance frequently occurs and severe side effects occur at high doses. DOX might induce activation of NF-κB causing this resistance, in which case proteasome inhibitors could inhibit activation of NF-κB by blocking inhibitory factor κB-alpha degradation. Triple-negative breast cancer (TNBC) is highly progressive and there are no established therapeutic targets against TNBC. Although some proteasome inhibitors have been shown to have antitumor effects in breast cancer, the effect of orally bioavailable proteasome inhibitor oprozomib on TNBC proliferation remains unclear. In the present study, we investigated the role of oprozomib in two TNBC lines, MDA-MB-231 and BT-549. Oprozomib had cytotoxic effects on TNBC cells and increased DOX-induced cytotoxic effects and apoptosis by enhancing DOX-induced JNK/p38 MAPK phosphorylation and inhibiting DOX-induced inhibitory factor êB alpha degradation. These results suggest that oprozomib has potent antitumor effects on TNBC in vitro and can sensitize TNBC cells to DOX treatment. The combination of DOX and oprozomib may be an effective and feasible therapeutic option for TNBC.

5.
Oncotarget ; 8(61): 104090-104103, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262623

RESUMO

Neuroblastoma (NB), the most common extracranial pediatric solid tumor, continues to cause significant cancer-related morbidity and mortality in children. Dysregulation of oncogenic receptor tyrosine kinases (RTKs) has been shown to contribute to tumorigenesis in various human cancers and targeting these RTKs has had therapeutic benefit. RET is an RTK which is commonly expressed in NB, and high expression of RET correlates with poor outcomes in patients with NB. Herein we report that RET is required for NB cell proliferation and that the small molecule inhibitor regorafenib (BAY 73-4506) blocks glial cell derived neurotrophic factor (GDNF)-induced RET signaling in NB cells and inhibits NB growth both in vitro and in vivo. We found that regorafenib significantly inhibited cell proliferation and colony formation ability of NB cells. Moreover, regorafenib suppressed tumor growth in both an orthotopic xenograft NB mouse model and a TH-MYCN transgenic NB mouse model. Finally, regorafenib markedly improved the overall survival of TH-MYCN transgenic tumor-bearing mice. In summary, our study suggests that RET is a potential therapeutic target in NB, and that using a novel RET inhibitor, like regorafenib, should be investigated as a therapeutic treatment option for children with NB.

6.
Cancer Lett ; 400: 61-68, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28455243

RESUMO

Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Carga Tumoral/efeitos dos fármacos , Quinase do Linfoma Anaplásico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Feminino , Predisposição Genética para Doença , Humanos , Concentração Inibidora 50 , Camundongos Nus , Camundongos Transgênicos , Mutação , Neuroblastoma/enzimologia , Neuroblastoma/genética , Neuroblastoma/patologia , Fenótipo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Oncotarget ; 8(20): 33666-33675, 2017 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-28430599

RESUMO

Aberrant activation of nuclear factor-κB (NF-κB) allows cancer cells to escape chemotherapy-induced cell death and acts as one of the major mechanisms of acquired chemoresistance in cervical cancer. TAK1, a crucial mediator that upregulates NF-κB activation in response to cellular genotoxic stress, is required for tumor cell viability and survival. Herein, we examined whether TAK1 inhibition is a potential therapeutic strategy for treating cervical cancer. We found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of Dox in a panel of cervical cancer cell lines. Treatment with 5Z-7-oxozeaenol hindered Dox-induced NF-κB activation and promoted Dox-induced apoptosis in cervical cancer cells. Moreover, 5Z-7-oxozeaenol showed similar effects in both positive and negative human papillomavirus-infected cervical cancer cells. Taken together, our results provide evidence that TAK1 inhibition significantly sensitizes cervical cancer cells to chemotherapy-induced cell death and supports the use of TAK1 inhibitor with current chemotherapies in the clinic for patients with refractory cervical cancer.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Zearalenona/análogos & derivados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo , Zearalenona/farmacologia
8.
Oncotarget ; 8(1): 1469-1480, 2017 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-27903968

RESUMO

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways. In addition, bosutinib enhanced doxorubicin (Dox)- and etoposide (VP-16)-induced cytotoxicity in NB cells. Furthermore, bosutinib demonstrated anti-tumor efficacy in an orthotopic xenograft NB mouse model in a similar mechanism as of that in vitro. In summary, our results reveal that Src and c-Abl are potential therapeutic targets in NB and that the novel Src/Abl inhibitor bosutinib alone or in combination with other chemotherapeutic agents may be a valuable therapeutic option for NB patients.


Assuntos
Compostos de Anilina/farmacologia , Neuroblastoma/tratamento farmacológico , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/metabolismo , Quinolinas/farmacologia , Quinases da Família src/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Criança , Humanos , Camundongos , Camundongos Nus , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidores
9.
Oncotarget ; 7(45): 73697-73710, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27655642

RESUMO

Proteasome inhibition is an attractive approach for anticancer therapy. Doxorubicin (DOX) is widely used for treatment in a number of cancers including breast cancer; however, the development of DOX resistance largely limits its clinical application. One of the possible mechanisms of DOX-resistance is that DOX might induce the activation of NF-κB. In this case, proteasome inhibitors could inhibit the activation of NF-κB by blocking inhibitory factor κB (IκB) degradation. Carfilzomib, a second-generation proteasome inhibitor, overcomes bortezomib resistance and lessens its side-effects. Currently, the effect of carfilzomib on breast cancer cell proliferation remains unclear. In this study, we exploited the role of carfilzomib in seven breast cancer cell lines, MCF7, T-47D, MDA-MB-361, HCC1954, MDA-MB-468, MDA-MB-231, and BT-549, representing all major molecular subtypes of breast cancer. We found that carfilzomib alone had cytotoxic effects on the breast cancer cells and it increased DOX-induced cytotoxic effects and apoptosis in combination by enhancing DOX-induced JNK phosphorylation and inhibiting DOX-induced IκBα degradation. The results suggest that carfilzomib has potent antitumor effects on breast cancer in vitro and can sensitize breast cancer cells to DOX treatment. DOX in combination with carfilzomib may be an effective and feasible therapeutic option in the clinical trials for treating breast cancer.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Oligopeptídeos/farmacologia , Inibidores de Proteassoma/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Sci Rep ; 6: 29090, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27378523

RESUMO

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is responsible for approximately 15% of cancer-related mortality in children. Aberrant activation of cyclin-dependent kinases (CDKs) has been shown to contribute to tumor cell progression in many cancers including NB. Therefore, small molecule inhibitors of CDKs comprise a strategic option in cancer therapy. Here we show that a novel multiple-CDK inhibitor, dinaciclib (SCH727965, MK-7965), exhibits potent anti-proliferative effects on a panel of NB cell lines by blocking the activity of CDK2 and CDK9. Dinaciclib also significantly sensitized NB cell lines to the treatment of chemotherapeutic agents such as doxorubicin (Dox) and etoposide (VP-16). Furthermore, dinaciclib revealed in vivo antitumor efficacy in an orthotopic xenograft mouse model of two NB cell lines and blocked tumor development in the TH-MYCN transgenic NB mouse model. Taken together, this study suggests that CDK2 and CDK9 are potential therapeutic targets in NB and that abrogating CDK2 and CDK9 activity by small molecules like dinaciclib is a promising strategy and a treatment option for NB patients.


Assuntos
Quinase 2 Dependente de Ciclina/genética , Quinase 9 Dependente de Ciclina/genética , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Neuroblastoma/genética , Neuroblastoma/patologia , Fosforilação/efeitos dos fármacos , Compostos de Piridínio/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mol Med Rep ; 13(2): 1869-80, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26718331

RESUMO

Survivin and transcription factor p65 (NF­κB p65) participate in the progression of esophageal squamous cell carcinoma (ESCC). However, the mechanism of NF­κB p65 activation in ESCC remains to be elucidated. The aim of the present study was to investigate the role of survivin in the activation of NF­κB p65 in ESCC. The expression levels of survivin, NF­κB p65, inhibitor of nuclear factor κB kinase subunit α (IKKα) and inhibitor of nuclear factor κB kinase subunit ß (IKKß) were detected in ESCC tissue samples. Eca109 and KYSE150 cells were cultured and survivin activity was modulated via transfection with an overexpression plasmid, a small hairpin RNA plasmid and a specific inhibitor. Quantitative reverse transcription-polymerase chain reaction and western blotting assays were conducted to assess the effects of survivin on the expression levels of IKKα, IKKß and NF­κB p65. Cell cycle and apoptosis assays were conducted to detect surviving-dependent cellular behavior changes. In addition, the luciferase reporter gene assay and chromatin immunoprecipitation assay were conducted to determine the genomic sites responsible for surviving-induced activation of NF­κB p65. The present study demonstrated that the expression of survivin is positively correlated with IKKα and IKKß in ESCC tissues. Survivin affected the mRNA and protein expression levels of IKKα, IKKß, and NF­κB p65 in Eca109 and KYSE150 cells. Furthermore, survivin increased the transcriptional activity of the IKKß promoter and bound to the IKKß promoter region in the Eca109 cells. Downregulation of survivin arrested the cell cycle at the G2/M phase and induced apoptosis. Results of the present study suggest that survivin activates NF­κB p65 in Eca109 cells via binding to the IKKß promoter region and upregulating IKKß promoter transcriptional activity. Survivin overexpression activates NF­κB p65, which is important in the acquisition and maintenance of the oncogenic characteristics of ESCC.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Quinase I-kappa B/genética , Proteínas Inibidoras de Apoptose/metabolismo , Regiões Promotoras Genéticas , Fator de Transcrição RelA/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Contagem de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Regulação para Baixo/efeitos dos fármacos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Imidazóis/farmacologia , Naftoquinonas/farmacologia , Ligação Proteica/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Survivina , Regulação para Cima/efeitos dos fármacos
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