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[PMID]:28460441
[Au] Autor:Arora J; Sauer SJ; Tarpley M; Vermeulen P; Rypens C; Van Laere S; Williams KP; Devi GR; Dewhirst MW
[Ad] Endereço:Duke Cancer Institute, Duke University, Durham, NC, USA.
[Ti] Título:Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies.
[So] Source:Oncotarget;8(16):25848-25863, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inflammatory breast cancer (IBC) is one of the most lethal breast cancer variants; with existing therapy, 5-yr survival rate is only 35%. Current barriers to successful treatment of IBC include frequent infiltration and the presence of tumor cell clusters, termed tumor emboli, within the breast parenchyma and lymphatics. Prior studies have identified the role of anti-apoptotic signaling, in particular hyperactivation of NFκB and its target genes, in IBC pathobiology and therapeutic resistance. The objectives of this study were to: (1) determine if IBC tumor emboli express anti-apoptotic proteins and (2) develop a high content, multiparametric assay to assess the morphology of the IBC 3D spheroids and to optimize a high throughput format to screen for compounds that can inhibit the formation of the IBC tumor clusters/embolic structures. Immunohistochemical analysis of IBC patient tumor samples with documented tumor emboli revealed high NFκB (p65) staining along with expression of XIAP, a potent anti-apoptotic protein known to interact with NFκB signaling in enhancing survival of malignant cells. Subsequently, the high content assay developed allowed for simultaneous imaging and morphometric analysis, including count and viability of spheroids derived from SUM149, rSUM149 and SUM190 cells and its application to evaluate XIAP and NFκB inhibitory agents. We demonstrate the efficacy of the off-patent drug disulfiram when chelated with copper, which we had previously reported to inhibit NFκB signaling, was highly effective in disrupting both IBC spheroids and emboli grown in vitro. Taken together, these results identify a high-throughput approach to target tumor spheroid formation for drug discovery. Finally, disulfiram is a safe and approved drug for management of alcohol abuse, warranting its evaluation for repurposing in IBC therapy.
[Mh] Termos MeSH primário: Proteínas Reguladoras de Apoptose/genética
Neoplasias Inflamatórias Mamárias/genética
Neoplasias Inflamatórias Mamárias/patologia
Células Neoplásicas Circulantes/metabolismo
[Mh] Termos MeSH secundário: Proteínas Reguladoras de Apoptose/metabolismo
Biomarcadores Tumorais
Técnicas de Cultura de Células
Sobrevivência Celular/genética
Cobre/farmacologia
Dissulfiram/farmacologia
Feminino
Expressão Gênica
Ensaios de Triagem em Larga Escala
Seres Humanos
Neoplasias Inflamatórias Mamárias/metabolismo
Mitocôndrias/metabolismo
NF-kappa B/genética
NF-kappa B/metabolismo
Esferoides Celulares
Células Tumorais Cultivadas
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoptosis Regulatory Proteins); 0 (Biomarkers, Tumor); 0 (NF-kappa B); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 789U1901C5 (Copper); TR3MLJ1UAI (Disulfiram)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15667


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[PMID]:29248579
[Au] Autor:Girardelli M; Basaldella F; Paolera SD; Vuch J; Tommasini A; Martelossi S; Crovella S; Bianco AM
[Ad] Endereço:Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'istria 65, Trieste, Italy.
[Ti] Título:Genetic profile of patients with early onset inflammatory bowel disease.
[So] Source:Gene;645:18-29, 2018 Mar 01.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).
[Mh] Termos MeSH primário: Predisposição Genética para Doença/genética
Doenças Inflamatórias Intestinais/genética
Polimorfismo de Nucleotídeo Único
Análise de Sequência de DNA/métodos
[Mh] Termos MeSH secundário: Idade de Início
Proteínas Relacionadas à Autofagia/genética
Criança
Pré-Escolar
Simulação por Computador
Feminino
Estudo de Associação Genômica Ampla
Seres Humanos
Lactente
Interleucina-10/genética
Masculino
Proteína Adaptadora de Sinalização NOD2/genética
Receptores de Interleucina/genética
Receptores de Interleucina-10/genética
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATG16L1 protein, human); 0 (Autophagy-Related Proteins); 0 (IL10 protein, human); 0 (IL23R protein, human); 0 (NOD2 protein, human); 0 (Nod2 Signaling Adaptor Protein); 0 (Receptors, Interleukin); 0 (Receptors, Interleukin-10); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 130068-27-8 (Interleukin-10)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:29277787
[Au] Autor:Miyamoto M; Takano M; Aoyama T; Soyama H; Ishibashi H; Kato K; Iwahashi H; Takasaki K; Kuwahara M; Matuura H; Sakamoto T; Yoshikawa T; Furuya K
[Ad] Endereço:Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Japan morikazu1118@hotmail.co.jp.
[Ti] Título:Phenoxodiol Increases Cisplatin Sensitivity in Ovarian Clear Cancer Cells Through XIAP Down-regulation and Autophagy Inhibition.
[So] Source:Anticancer Res;38(1):301-306, 2018 01.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: To investigate whether XIAP down-regulation and autophagy inhibition sensitize ovarian clear cell cancer cells to cisplatin. MATERIALS AND METHODS: The ovarian clear cancer cell line KK was used for in vitro analysis. Hydroxychloroquine (HCQ) and phenoxodiol (PXD) or embelin were used as autophagy and XIAP inhibitors, respectively. Non-specific and XIAP-specific siRNAs were transfected using Lipofectamine. Cytotoxicity was assessed by MTT assays. Protein expression was confirmed by western blotting. RESULTS: In KK, down-regulation of XIAP using specific siRNAs together with HCQ treatment enhanced the anti-tumor effect of cisplatin. Although embelin sensitized KK to cisplatin through XIAP down-regulation, it induced autophagy. However, PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition. Expression of Atg7, Atg12, and Beclin 1 was decreased after PXD treatment. CONCLUSION: PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition and could be a new candidate for ovarian clear cell carcinoma treatment.
[Mh] Termos MeSH primário: Adenocarcinoma de Células Claras/metabolismo
Antineoplásicos/farmacologia
Cisplatino/farmacologia
Isoflavonas/farmacologia
Neoplasias Ovarianas/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Mh] Termos MeSH secundário: Adenocarcinoma de Células Claras/genética
Autofagia/efeitos dos fármacos
Benzoquinonas/farmacologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Regulação para Baixo
Feminino
Seres Humanos
Neoplasias Ovarianas/genética
RNA Interferente Pequeno/genética
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzoquinones); 0 (Isoflavones); 0 (RNA, Small Interfering); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 995FT1W541 (phenoxodiol); Q20Q21Q62J (Cisplatin); SHC6U8F5ER (embelin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE


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[PMID]:29236891
[Au] Autor:Tirapelli DPDC; Lustosa IL; Menezes SB; Franco IM; Rodrigues AR; Peria FM; Marinho AMDN; Serafini LN; Carlotti CG; Tirapelli LF
[Ad] Endereço:Universidade de São Paulo, Departamento de Cirurgia e Anatomia, Ribeirão Preto SP, Brasil.
[Ti] Título:High expression of XIAP and Bcl-2 may inhibit programmed cell death in glioblastomas.
[So] Source:Arq Neuropsiquiatr;75(12):875-880, 2017 Dec.
[Is] ISSN:1678-4227
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:Glioblastoma (GBM) is the most malignant glioma and represents 29% of all brain tumors. Tumorigenesis is intimately connected with characteristics acquired in the physiologic pathway of cellular death. OBJECTIVE: In the present study, the expression of anti-apoptotic (XIAP and Bcl-2) and apoptotic (cytochrome C, caspase 9, APAF-1), caspase 3 and the Smac/DIABLO genes related to the apoptosis pathway were evaluated in 30 samples of glioblastoma. METHODS: The gene expression was evaluated in 30 glioblastomas (WHO grade IV) and compared to 10 white matter control samples with real-time PCR. RESULTS AND CONCLUSION: There were higher expressions of XIAP (p = 0.0032) and Bcl-2 (p = 0.0351) in the glioblastoma samples compared to the control samples of normal brain. These results raise the question of whether Bcl-2 and XIAP genes can be responsible for the inhibition of programmed cell death in glioblastomas. Moreover, they provide additional information capable of allowing the development of new target therapy strategies.
[Mh] Termos MeSH primário: Apoptose
Neoplasias Encefálicas/metabolismo
Regulação Neoplásica da Expressão Gênica
Glioblastoma/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Mh] Termos MeSH secundário: Neoplasias Encefálicas/genética
Neoplasias Encefálicas/patologia
Linhagem Celular Tumoral
Feminino
Glioblastoma/genética
Glioblastoma/patologia
Seres Humanos
Masculino
Meia-Idade
Proteínas Proto-Oncogênicas c-bcl-2/genética
Reação em Cadeia da Polimerase em Tempo Real
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proto-Oncogene Proteins c-bcl-2); 0 (X-Linked Inhibitor of Apoptosis Protein)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE


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[PMID]:29053960
[Au] Autor:Gabrielsen M; Buetow L; Nakasone MA; Ahmed SF; Sibbet GJ; Smith BO; Zhang W; Sidhu SS; Huang DT
[Ad] Endereço:Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
[Ti] Título:A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants.
[So] Source:Mol Cell;68(2):456-470.e10, 2017 Oct 19.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site. Surprisingly, the UbV selective for dimeric XIAP formed a dimer to stimulate E3 activity by stabilizing the closed E2∼Ub conformation. We further verified the inhibitory and stimulatory functions of UbVs in cells. Our work provides a general strategy to inhibit or activate RING/U-box E3 ligases and provides a resource for the research community to modulate these enzymes.
[Mh] Termos MeSH primário: Descoberta de Drogas/métodos
Ativadores de Enzimas
Inibidores Enzimáticos
Multimerização Proteica/efeitos dos fármacos
Proteínas Supressoras de Tumor
Complexos Ubiquitina-Proteína Ligase
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X
[Mh] Termos MeSH secundário: Ativadores de Enzimas/química
Ativadores de Enzimas/farmacologia
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Células HEK293
Células HeLa
Seres Humanos
Proteínas Supressoras de Tumor/agonistas
Proteínas Supressoras de Tumor/antagonistas & inibidores
Proteínas Supressoras de Tumor/genética
Proteínas Supressoras de Tumor/metabolismo
Complexos Ubiquitina-Proteína Ligase/antagonistas & inibidores
Complexos Ubiquitina-Proteína Ligase/genética
Complexos Ubiquitina-Proteína Ligase/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/agonistas
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Activators); 0 (Enzyme Inhibitors); 0 (Tumor Suppressor Proteins); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); EC 2.3.2.23 (Ubiquitin-Protein Ligase Complexes); EC 6.3.2.- (UBE4B protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE


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[PMID]:29017180
[Au] Autor:Cassier PA; Castets M; Belhabri A; Vey N
[Ad] Endereço:Department of Medical Oncology, Centre Léon Bérard, 69008 Lyon, France.
[Ti] Título:Targeting apoptosis in acute myeloid leukaemia.
[So] Source:Br J Cancer;117(8):1089-1098, 2017 Oct 10.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease, and its incidence is increasing as the populations in Western countries age. Despite major advances in understanding the genetic landscape of AML and its impact on the biology of the disease, standard therapy has not changed significantly in the last three decades. Allogeneic haematopoietic stem cell transplantation remains the best chance for cure, but can only be offered to a minority of younger fit patients. Molecularly targeted drugs aiming at restoring apoptosis in leukaemic cells have shown encouraging activity in early clinical trials and some of these drugs are currently being evaluated in randomised controlled trials. In this review, we discuss the current development of drugs designed to trigger cell death in AML.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Apoptose
Proteínas Inibidoras de Apoptose/antagonistas & inibidores
Leucemia Mieloide Aguda/terapia
Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores
[Mh] Termos MeSH secundário: Transplante de Células-Tronco Hematopoéticas
Seres Humanos
Terapia de Alvo Molecular
Receptores do Ligante Indutor de Apoptose Relacionado a TNF
Proteína Supressora de Tumor p53
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Inhibitor of Apoptosis Proteins); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand); 0 (Tumor Suppressor Protein p53); 0 (X-Linked Inhibitor of Apoptosis Protein); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.281


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[PMID]:28792527
[Au] Autor:Cai J; Wang D; Bai ZG; Yin J; Zhang J; Zhang ZT
[Ad] Endereço:Department of General Surgery, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China.
[Ti] Título:The long noncoding RNA XIAP-AS1 promotes XIAP transcription by XIAP-AS1 interacting with Sp1 in gastric cancer cells.
[So] Source:PLoS One;12(8):e0182433, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Long noncoding RNAs (lncRNAs) play roles in the tumorigenesis, proliferation and metastasis of tumor cells. Previous studies indicate that the transcription factor Sp1 is responsible for transcription of the XIAP gene, but it is unknown whether lncRNAs are involved in XIAP transcription. Herein, we identified a novel lncRNA, denoted as XIAP-AS1, transcribed from the first intron of the complementary strand of the XIAP gene. Using RNA FISH, cell fractionation and qRT-PCR, XIAP-AS1 was determined to be located primarily in the nucleus. After various XIAP-AS1 deletion mutants were expressed, RIP assays showed that only the full-length XIAP-AS1 RNA interacted with Sp1 and thereby participated in XIAP transcription. ChIP assays showed that XIAP-AS1 knockdown decreased the binding of Sp1 to the promoter region of XIAP. XIAP-AS1 knockdown promoted tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in gastric tumor cells, as cleaved caspase-3 and caspase-9 was detected. Moreover, in an in vivo mouse xenograft model, tumor cell proliferation was inhibited by XIAP-AS1 knockdown in response to TRAIL administration. In conclusion, our results indicate that XIAP-AS1 is involved in XIAP transcription by interacting with Sp1. Additionally, XIAP-AS1 is a potential target for TRAIL-induced apoptosis in gastric cancer cells.
[Mh] Termos MeSH primário: RNA Longo não Codificante/metabolismo
Fator de Transcrição Sp1/metabolismo
Neoplasias Gástricas/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/fisiologia
Carcinogênese/metabolismo
Linhagem Celular Tumoral
Núcleo Celular/metabolismo
Núcleo Celular/patologia
Proliferação Celular/fisiologia
Citoplasma/metabolismo
Citoplasma/patologia
Feminino
Regulação Neoplásica da Expressão Gênica/fisiologia
Técnicas de Silenciamento de Genes
Seres Humanos
Camundongos Endogâmicos BALB C
Camundongos Nus
Transplante de Neoplasias
Regiões Promotoras Genéticas
RNA Longo não Codificante/genética
Neoplasias Gástricas/patologia
Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Long Noncoding); 0 (Sp1 Transcription Factor); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (TNFSF10 protein, human); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 0 (long noncoding RNA XIAP-AS1, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182433


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[PMID]:28756806
[Au] Autor:Huang WS; Xu FM; Zeng QZ; Liu XH; Gao XJ; Liu LX
[Ad] Endereço:Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou 510632, Guangdong, China.
[Ti] Título:ERK1/2-mediated Cytoplasmic Accumulation of hnRNPK Antagonizes TRAIL-induced Apoptosis through Upregulation of XIAP in H1299 Cells.
[So] Source:Biomed Environ Sci;30(7):473-481, 2017 Jul.
[Is] ISSN:0895-3988
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance greatly limits the clinical therapeutic efficacy of TRAIL. Elucidating the molecular mechanism underlying TRAIL resistance will be fundamental to resolving this problem. METHODS: Nuclear and cytoplasmic protein extraction and immuno?uorescence (IF) assay were used to detect changes in heterogeneous nuclear ribonucleoprotein K (hnRNPK) localization in H1299 cells. The evaluation of cell apoptosis in cells transfected with GFP-hnRNPK, GFP-hnRNPK S284/353A, or GFP-hnRNPK S284/353D mutant was performed using cleaved caspase-3 antibody. The gene expression of XIAP was tested by quantitative RT-PCR. RESULTS: Previously, we reported that hnRNPK antagonized TRAIL-induced apoptosis through inhibition of PKC-mediated GSK3ß phosphorylation. In this study, we further demonstrate that TRAIL treatment induces cytoplasmic accumulation of hnRNPK in H1299 cells. The hnRNPK localized in the cytoplasm has a higher capacity to antagonize TRAIL-induced apoptosis. Both ERK1/2 signaling inhibitor U0126 and ERK-phosphoacceptor-site mutant (GFP-hnRNPK S284/353A) diminish cytoplasmic accumulation of hnRNPK induced by TRAIL. Moreover, we show that XIAP is involved in hnRNPK-mediated TRAIL resistance in H1299 cells. CONCLUSION: Taken together, these results give new insights into the understanding of the molecular mechanism associated with TRAIL resistance in lung adenocarcinoma.
[Mh] Termos MeSH primário: Apoptose/fisiologia
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Regulação da Expressão Gênica/fisiologia
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
Seres Humanos
Proteína Quinase 1 Ativada por Mitógeno/genética
Proteína Quinase 3 Ativada por Mitógeno/genética
Ligante Indutor de Apoptose Relacionado a TNF/genética
Regulação para Cima/fisiologia
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (TNFSF10 protein, human); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 146410-60-8 (HNRNPK protein, human); EC 2.7.11.24 (MAPK1 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.3967/bes2017.063


  9 / 1845 MEDLINE  
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[PMID]:28739697
[Au] Autor:Shiomi Y; Yoshimura M; Kuki K; Hori Y; Tanaka T
[Ad] Endereço:Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd., Kumagaya, Japan yoshihiro-shiomi@zeria.co.jp.
[Ti] Título:Z-360 Suppresses Tumor Growth in MIA PaCa-2-bearing Mice Inhibition of Gastrin-induced Anti-Apoptotic Effects.
[So] Source:Anticancer Res;37(8):4127-4137, 2017 08.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: The aim of the study was to evaluate the anti-tumor mechanism of Z-360, a gastrin/cholecystokinin-2 receptor (CCK2R) antagonist, in MIA PaCa-2 cells and in a subcutaneous xenograft mice model. MATERIALS AND METHODS: The anti-tumor effects of Z-360 and/or gemcitabine were monitored using a MIA PaCa-2 xenograft model. The effect of Z-360 on apoptosis in the model was examined by TUNEL staining and real-time PCR analysis and the effect in MIA PaCa-2 cells stably expressing human CCK2R was also evaluated by caspase-3/7 activity. RESULTS: In this xenograft model, Z-360 significantly reduced the tumor weight, increased TUNEL-positive cells and suppressed the expression of anti-apoptosis factors such as survivin, XIAP and Mcl-1, and these effects of Z-360 combined with gemcitabine were more effective. Furthermore, gastrin-17 and gastrin-34 inhibited apoptosis in vitro and Z-360 dose-dependently abrogated this effect. CONCLUSION: These results suggest that Z-360 exerts an anti-tumor effect through a reduction in anti-apoptosis factors by blocking CCK2R.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Benzodiazepinonas/administração & dosagem
Neoplasias Pancreáticas/tratamento farmacológico
Receptor de Colecistocinina B/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Desoxicitidina/administração & dosagem
Desoxicitidina/análogos & derivados
Endopeptidases/administração & dosagem
Gastrinas/administração & dosagem
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Proteínas Inibidoras de Apoptose/biossíntese
Camundongos
Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/patologia
Receptor de Colecistocinina B/antagonistas & inibidores
Receptor de Colecistocinina B/biossíntese
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/biossíntese
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BIRC5 protein, human); 0 (Benzodiazepinones); 0 (Gastrins); 0 (Inhibitor of Apoptosis Proteins); 0 (MCL1 protein, human); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Receptor, Cholecystokinin B); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 0 (Z-360); 0W860991D6 (Deoxycytidine); 60748-06-3 (gastrin 17); B76N6SBZ8R (gemcitabine); EC 3.4.- (Endopeptidases); EC 3.4.99.- (gastrinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


  10 / 1845 MEDLINE  
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[PMID]:28704451
[Au] Autor:Prabhu KS; Siveen KS; Kuttikrishnan S; Iskandarani A; Tsakou M; Achkar IW; Therachiyil L; Krishnankutty R; Parray A; Kulinski M; Merhi M; Dermime S; Mohammad RM; Uddin S
[Ad] Endereço:Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, State of Qatar.
[Ti] Título:Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells.
[So] Source:PLoS One;12(7):e0180895, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The X-linked inhibitor of apoptosis (XIAP) is a viable molecular target for anticancer drugs that overcome apoptosis-resistance of malignant cells. XIAP is an inhibitor of apoptosis, mediating through its association with BIR3 domain of caspase 9. Embelin, a quinone derivative isolated from the Embelia ribes plant, has been shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities via inhibiting XIAP activity. In this study, we found that embelin causes a dose-dependent suppression of proliferation in leukemic cell lines K562 and U937. Embelin mediated inhibition of proliferation correlates with induction of apoptosis. Furthermore, embelin treatment causes loss of mitochondrial membrane potential and release of cytochrome c, resulting in subsequent activation of caspase-3 followed by polyadenosin-5'-diphosphate-ribose polymerase (PARP) cleavage. In addition, embelin treatment of leukemic cells results in a decrease of constitutive phosphorylations/activation level of AKT and downregulation of XIAP. Gene silencing of XIAP and AKT expression showed a link between XIAP expression and activated AKT in leukemic cells. Interestingly, targeting of XIAP and PI3-kinase/AKT signaling augmented inhibition of proliferation and induction of apoptosis in leukemic cells. Altogether these findings raise the possibility that embelin alone or in combination with inhibitors of PI3-kinase/AKT pathway may have therapeutic usage in leukemia and possibly other malignancies with up-regulated XIAP pathway.
[Mh] Termos MeSH primário: Benzoquinonas/farmacologia
Cromonas/farmacologia
Leucemia/metabolismo
Morfolinas/farmacologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Sinergismo Farmacológico
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Células K562
Leucemia/tratamento farmacológico
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoquinones); 0 (Chromones); 0 (Morpholines); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); SHC6U8F5ER (embelin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180895



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