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1.
Clin Oral Investig ; 27(8): 4335-4344, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37157029

RESUMEN

OBJECTIVES: Bacteria derived from the oral cavity enter the bloodstream and cause the onset of various systemic diseases, including heart valve disease. However, information on the oral bacteria involved in aortic stenosis is limited. MATERIALS AND METHODS: We comprehensively analyzed the microbiota in aortic valve tissues collected from aortic stenosis patients using metagenomic sequencing and investigated the relationships between the valve microbiota, the oral microbiota, and oral cavity conditions. RESULTS: Metagenomic analysis revealed the presence of 629 bacterial species in five oral plaques and 15 aortic valve clinical specimens. Patients were classified into two groups (A and B) according to their aortic valve microbiota composition using principal coordinate analysis. Examination of the oral conditions of the patients showed no difference in the decayed/missing/filled teeth index. Bacteria in group B tend to be associated with severe disease, and the number of bacteria on the dorsum of the tongue and the positive rate of bleeding during probing were significantly higher in this group than in group A. The pathophysiology of aortic stenosis may be related to the presence of oral bacteria such as Streptococcus oralis and Streptococcus sanguinis following bacteremia. CONCLUSIONS: Systemic inflammation in severe periodontitis may be driven by the oral microbiota, supporting the indirect (inflammatory) association between oral bacteria and aortic stenosis. CLINICAL RELEVANCE: Appropriate oral hygiene management may contribute to the prevention and treatment of aortic stenosis.


Asunto(s)
Estenosis de la Válvula Aórtica , Microbiota , Humanos , Válvula Aórtica/microbiología , Bacterias/genética , Boca/microbiología , Estenosis de la Válvula Aórtica/microbiología
2.
Oncol Rep ; 49(5)2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36896788

RESUMEN

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, in Fig. 4 on p. 650, the same ß­actin bands had apparently been used to show the experimental effects of the proteasome inhibitor MG­132 on c­FLIP in HSC­2 cells in Fig. 4A, and the effects of MG­132 on IAPs in HSC­3 cells in Fig. 4B. In addition, for the fourth lane in the gel showing the effects of MG­132 on c­FLIP in HSC­3 cells, this should have been labelled as '+MG­132 / +TRAIL' (not as '­/­'). Upon contacting the authors in relation to this matter, they could only admit that errors had been made in the preparation of the figure; moreover, they no longer had access to the original data owing to the time that has elapsed since the publication of the paper, and it would be impossible for them to now repeat this experiment. After having considered this matter and in conjunction with a request made by the authors, the Editor of Oncology Reports has decided that this paper should be retracted from the publication. Both the Editor and the authors apologize to the readership for any inconvenience caused. [Oncology Reports 25: 645­652, 2011; DOI: 10.3892/or.2010.1127].

3.
J Oral Maxillofac Surg ; 75(2): 440.e1-440.e9, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27765548

RESUMEN

Phyllodes tumor is a rare breast tumor described by Müller (1938) as a lesion comprising leaflike stromal fibrous components and narrow cysts. The frequency of distant metastasis from this entity is reportedly approximately 20%, and no effective therapy has been established, so the prognosis is poor. This report describes the case of a 60-year-old woman with a history of left lung resection who showed metastasis of a mammary gland malignant phyllodes tumor to the oral cavity. Intraoral examination showed an elastic, hard mass measuring 28 × 27 mm in the gingiva around the left mandibular second molar. Biopsy examination showed growth of giant cells and roughly circular cells showing positivity for S-100, p63, and vimentin on immunohistochemical staining. The authors diagnosed metastasis of the mammary gland malignant phyllodes tumor to the left mandible and performed cyber knife irradiation (44 Gy in 5 fractions) of the left mandible. The mass in the oral cavity disappeared after cyber knife irradiation, but the patient died of direct invasion to the spine.


Asunto(s)
Neoplasias de la Mama/patología , Neoplasias Gingivales/secundario , Neoplasias Mandibulares/secundario , Tumor Filoide/patología , Neoplasias de la Mama/cirugía , Femenino , Neoplasias Gingivales/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Neoplasias Mandibulares/diagnóstico por imagen , Persona de Mediana Edad , Tumor Filoide/cirugía , Radiografía , Tomografía Computarizada por Rayos X
4.
Anticancer Res ; 33(10): 4309-17, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24122997

RESUMEN

AIM: Enhancer of zeste homolog-2 (EZH2) and B lymphoma Mo-MLV insertion region-1 homolog (BMI1) are members of the polycomb group of proteins, which function as transcriptional repressors through chromatin modification. EZH2 forms part of the polycomb repressive complex (PRC)-2, while BMI1 is a component of PRC1. Previous studies have shown that EZH2 is highly expressed in various type of cancers. Expression of EZH2 is reported to be regulated by the P53-E2F/retinoblastoma (RB)-related pathway, and a correlation between P53 mutation and EZH2 expression was recently found in breast cancer. Here, we examined the relationship between P53 and EZH2 in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Using immunohistochemistry, we investigated the expression of EZH2 and BMI1 in 99 surgically-resected OSCC and 34 epithelial dysplasia samples. We analyzed associations between aberrant expression of EZH2 and BMI1, and clinicopathological findings and patient outcome. P53 expression was also examined and analyzed in relation to EZH2 and BMI1 expression. RESULTS: EZH2 and BMI1 protein were up-regulated in OSCC tissues compared with epithelial dysplasia and normal epithelium. Aberrant EZH2 and BMI1 protein expression was observed in 32 and 59 of the 99 OSCC samples, respectively. Aberrant EZH2 and BMI1 expression was significantly associated with mode of invasion, but not with lymph node metastasis or survival rate. Aberrant EZH2 expression was associated with P53 alteration in OSCC tissue. Expression of EZH2 mRNA in SAS/neo cells, which have wild-type P53, was significantly lower than in SAS/mp53 cells that have a mutant P53 gene. CONCLUSION: P53 alteration may be involved in dysregulated EZH2 expression, and aberrant expression of EZH2 may play a role in carcinogenesis of OSCC.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Neoplasias de la Boca/metabolismo , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 2/metabolismo , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Línea Celular Tumoral , Núcleo Celular/metabolismo , Supervivencia sin Enfermedad , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Expresión Génica , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/patología , Mutación , Invasividad Neoplásica , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 2/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba
5.
Oncol Rep ; 30(2): 579-83, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23708842

RESUMEN

microRNAs (miRNAs) are involved in cancer pathogenesis, apoptosis and cell growth, thereby functioning as both tumor suppressors and oncogenes. However, the expression patterns and roles of miRNAs in oral squamous cell carcinoma (OSCC) remain largely unknown. We hypothesized that oral cancer may have a unique miRNA profile, which in turn may play a critical role in oral cancer development, progression, diagnosis and prognosis. We, therefore, investigated the expression profiles of 29 OSCC tumors and 7 normal oral mucosal samples. The miRNA expression patterns in OSCC were examined by TaqMan-based microRNA assays. We were subsequently able to identify the candidates of cancer-related miRNAs through analysis of the miRNA expression profiles. In conclusion, OSCC tissues were shown to have a unique miRNA profile pattern when compared with that in normal tissues. The present study may provide useful information for further investigation of the functional roles of miRNAs in OSCC development, progression, diagnosis and prognosis.


Asunto(s)
Carcinoma de Células Escamosas/genética , MicroARNs/biosíntesis , Neoplasias de la Boca/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Pronóstico , Transcriptoma
6.
Hum Mol Genet ; 20(14): 2710-21, 2011 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-21505077

RESUMEN

Epigenetic regulation is essential in determining cellular phenotypes during differentiation. Although tissue-specific DNA methylation has been studied, the significance of methylation variance for tissue phenotypes remains unresolved, especially for CpG-poor promoters. Here, we comprehensively studied methylation levels of 27 578 CpG sites among 21 human normal tissues from 12 anatomically different regions using an epigenotyping beadarray system. Remarkable changes in tissue-specific DNA methylation were observed within CpG-poor promoters but not CpG-rich promoters. Of note, tissue-specific hypomethylation is accompanied by an increase in gene expression, which gives rise to specialized cellular functions. The hypomethylated regions were significantly enriched with recognition motifs for transcription factors that regulate cell-type-specific differentiation. To investigate the dynamics of hypomethylation events, we analyzed methylation levels of the entire APOA1 gene locus during in vitro differentiation of embryonic stem cells toward the hepatic lineage. A decrease in methylation was observed after day 13, coinciding with alpha-fetoprotein detection, in the vicinity of its transcription start sites (TSSs), and extends up to ∼200 bp region encompassing the TSS at day 21, equivalent to the hepatoblastic stage. This decrease is even more pronounced in the adult liver, where the entire APOA1 gene locus is hypomethylated. Furthermore, when we compared the methylation status of induced pluripotent stem (iPS) cells with their parental cell, IMR-90, we found that fibroblast-specific hypomethylation is restored to a fully methylated state in iPS cells after reprogramming. These results illuminate tissue-specific methylation dynamics in CpG-poor promoters and provide more comprehensive views on spatiotemporal gene regulation in terminal differentiation.


Asunto(s)
Diferenciación Celular/fisiología , Islas de CpG/fisiología , Metilación de ADN/fisiología , Regiones Promotoras Genéticas/fisiología , Adulto , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Especificidad de Órganos/fisiología
7.
Oncol Rep ; 25(3): 645-52, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21206980

RESUMEN

Oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture. We investigated the role of a proteaosome inhibitor in the survival and apoptosis of these cells. We found that the proteasome inhibitor MG132 markedly accelerated TRAIL-mediated apoptosis in OSCC cell lines HSC-2 and HSC-3. Addition of TRAIL to MG132-treated cells resulted in Bid cleavage. Furthermore, the inhibitors of caspase-3, caspase-8 and caspase-9 reduced the accelerative effect of MG132 on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of a proteasome inhibitor on TRAIL-mediated apoptosis may contribute to both extrinsic and intrinsic pathways. MG132 enhanced the expression of the TRAIL receptors DR4 and DR5, and neutralization of DR5 receptors showed a marked reduction of TRAIL-mediated apoptosis, whereas that of DR4 was a partial reduction. MG132 also markedly reduced cellular FLICE-inhibitory protein (c-FLIP), cellular inhibitor of apoptosis protein-1 (cIAP-1), X-linked IAP (XIAP) and survivin. Therefore, MG132 provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of DR5, c-FLIP, cIAP-1, XIAP and survivin. The proteasome inhibitor MG132 may therefore represent a novel strategy for overcoming resistance to TRAIL-mediated apoptosis in OSCC cells.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Leupeptinas/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Ligando Inductor de Apoptosis Relacionado con TNF/administración & dosificación , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Inhibidores de Cisteína Proteinasa/administración & dosificación , Inhibidores de Cisteína Proteinasa/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Humanos , Leupeptinas/administración & dosificación , Neoplasias de la Boca/patología , Inhibidores de Proteasoma , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico
8.
Oral Oncol ; 45(9): 766-70, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19157955

RESUMEN

It has been reported recently that histone deacetylase inhibitors (HDACIs) can block the growth of a variety of malignant tumor cells by reversing the silencing of the tumor suppressor genes; these will be the anticancer agents of the next generation. In this study, we evaluated the antitumor effects of the HDACI suberoylanilide hydroxamic acid (SAHA) on oral squamous cell carcinoma (OSCC) and investigated its molecular mechanism. SAHA suppressed the in vitro proliferation of OSCC cell lines in a dose- and time-dependent manner. Flow cytometric analyses showed that treatment with SAHA led to G1 phase cell-cycle arrest of OSCC cells, accompanying a decrease in the percentage of S-phase cells. Western blot analyses demonstrated that the expression of p21 protein was remarkably augmented and hyperacetylation of p53 was induced after SAHA treatment. These results suggest that administration of SAHA suppresses OSCC growth through G1 phase arrest. Additionally, we observed that the growth of xenograft SAS tumors in nude mice was significantly blocked by the administration of SAHA without major adverse effects.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Ácidos Hidroxámicos/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Animales , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Fase G1/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Fase S/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Vorinostat
9.
Oral Oncol ; 45(2): 109-15, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18710819

RESUMEN

Malignant tumors are exposed to various levels of hypoxic condition in vivo. It has been known that tumor cells under hypoxia are resistant to chemotherapies. To clarify the mechanism of the hypoxia-induced chemoresistance, we evaluated the effects of hypoxia on the resistance of oral squamous cell carcinoma (OSCC) cell lines to 5-fluorouracil (5-FU). OSCC cells were divided to two groups by the proliferation activity under hypoxic condition; hypoxia-resistant (HR) and hypoxia-sensitive (HS) cells. Growth of HS cells were inhibited by hypoxia and introduced to G(1) arrest in cell cycle. 5-FU effect on HS cell viability was markedly reduced in hypoxic condition without an induction of chemoresistant related protein, P-glycoprotein. However, proliferation, cell cycle, and 5-FU sensitivity of HR cells were not affected by hypoxia. Hypoxia-inducible factor (HIF)-1alpha was induced by hypoxia in all OSCC cell lines, but diminished in HS cells within 48h. Expression of p21 and p27 was strongly augmented and CyclinD expression was reduced by hypoxia in HS cells. However, the expression of these proteins was constitutive in HR cells during 48h hypoxic culture. Phosphorylation of mammalian target of rapamycin (mTOR) was reduced by hypoxia in HS cells. From these findings, we concluded that HS OSCC cells acquire 5-FU resistance under hypoxia by G(1)/S transition through an upregulation of cell cycle inhibitors.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Hipoxia de la Célula/fisiología , Resistencia a Antineoplásicos/fisiología , Fluorouracilo/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/fisiología , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Proliferación Celular/efectos de los fármacos , Ciclina D/metabolismo , Fase G1/efectos de los fármacos , Fase G1/fisiología , Humanos , Neoplasias de la Boca/metabolismo , Factores de Transcripción/metabolismo
10.
Oral Oncol ; 44(4): 361-8, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17689285

RESUMEN

Molecular inhibition of epidermal growth factor receptor (EGFR) signaling is a promising cancer treatment strategy. We examined whether inhibition of EGFR signaling would affect the susceptibility of oral squamous cell carcinoma (OSCC) cells to Fas-mediated apoptosis. Treatment of OSCC cells with an anti-EGFR monoclonal antibody, C225, and an EGFR tyrosine kinase inhibitor, AG1478, which target the extracellular and intracellular domains of the receptor, respectively, inhibited phosphorylation of EGFR and its downstream effector molecule Akt and amplified the induction of Fas-mediated apoptosis. In OSCC cells treated with EGFR inhibitors, Fas-mediated apoptosis was accompanied by caspase-8 activation but not Bid cleavage. Caspase-3 and -8 inhibitors reduced the effect of EGFR inhibitors on Fas-mediated apoptosis in OSCC cells, but a caspase-9 inhibitor did not. These results indicate that the pro-apoptotic activity of EGFR inhibitors in OSCC cells depends on the extrinsic pathway of the caspase cascade. Although EGFR inhibitors did not affect the expression of Fas, the Fas-associated death domain protein, or procaspase-8 in OSCC cells, the inhibition downregulated cellular FLICE-inhibitory protein (c-FLIP). Moreover, knockdown of c-FLIP in HSC-2 cells with a small interfering RNA strongly enhanced Fas-mediated apoptosis. These results suggest that the EGFR signaling pathway may, in part, regulate Fas-mediated apoptosis in OSCC cells through c-FLIP expression.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/patología , Receptores ErbB/antagonistas & inhibidores , Neoplasias de la Boca/patología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Carcinoma de Células Escamosas/metabolismo , Caspasa 8/metabolismo , Cetuximab , Inhibidores Enzimáticos/farmacología , Receptores ErbB/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Humanos , Neoplasias de la Boca/metabolismo , Proteínas de Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinazolinas , Células Tumorales Cultivadas , Tirfostinos/farmacología , Receptor fas/metabolismo , Receptor fas/fisiología
11.
Int J Oncol ; 31(5): 1141-7, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17912441

RESUMEN

The purpose of this study was to determine whether phosphatidylinositol 3-kinase (PI 3-K) inhibitors could modulate the apoptotic activity of the anticancer drugs cisplatin, 5-fluorouracil or docetaxel in an oral squamous cell carcinoma (OSCC) cell line, HSC-2. In preliminary experiments, cisplatin, 5-fluorouracil and docetaxel inhibited the proliferation of OSCC cells in a dose-dependent manner. We found that two PI 3-K inhibitors, wortmannin and LY294002, markedly suppressed the phosphorylation of Akt in OSCC cells. Treatment of OSCC cells with PI 3-K inhibitors significantly enhanced cisplatin-, 5-fluorouracil- or docetaxel-induced apoptosis. Caspase-3 and -9 inhibitors, but not a caspase-8 inhibitor, reduced anticancer drug-mediated apoptosis in PI 3-K inhibitor-treated OSCC cells, suggesting that the apoptotic pathway induced by the combination of anticancer drug therapy and PI 3-K inhibition may be functionally related to the intrinsic apoptotic pathway in OSCC cells. Expression of Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1), and X-linked IAP was down-regulated, and expression of Bax was up-regulated by PI 3-K inhibitors, while that of Bcl-xL, Bak and cIAP-2 was not attenuated. We also found that Bad phosphorylation was down-regulated by PI 3-K inhibitors. These results suggested that inhibition of PI 3-K enhances the susceptibility of OSCC cells to anticancer drug-mediated apoptosis through regulation of expression and post-translational modification of both pro- and anti-apoptotic proteins. These findings could potentially lead to new strategies for improving the efficacy of anticancer drugs in OSCC cells.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Neoplasias de la Boca/patología , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína Letal Asociada a bcl/metabolismo
12.
Int J Oncol ; 30(6): 1469-76, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17487368

RESUMEN

Epidermal growth factor (EGF) is known to be involved in the proliferation and metastasis of squamous cell carcinoma (SCC), suggesting that the EGF receptor (EGFR) must also contribute to SCC development. In combination with conventional anti-cancer drugs, agents that block EGFR may represent an efficient means of inhibiting proliferation and inducing apoptosis in SCC cells. We investigated the effects of combining an anti-EGFR monoclonal antibody (C225) or an EGFR-selective tyrosine kinase inhibitor (AG1478) with the conventional anti-cancer drug cisplatin on the oral SCC (OSCC) cell lines NA and Ca9-22. We detected constitutive expression of EGFR on the cell membranes of both cell lines. OSCC cell proliferation was inhibited by C225, AG1478 and cisplatin in a dose-dependent manner. The combination of C225 or AG1478 with cisplatin at concentrations

Asunto(s)
Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Cisplatino/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Tirfostinos/farmacología , Anticuerpos Monoclonales Humanizados , Apoptosis/efectos de los fármacos , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cetuximab , Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Humanos , Proteínas Inhibidoras de la Apoptosis/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/efectos de los fármacos , Quinazolinas
13.
Int J Oncol ; 30(5): 1163-71, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17390018

RESUMEN

In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture in vitro. Here, we studied the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt in survival and apoptosis of these cells. The PI 3-K inhibitors wortmannin and LY294002 markedly suppressed phosphorylation of Akt and accelerated TRAIL-mediated apoptosis in OSCC cells. Addition of TRAIL to PI 3-K inhibitor-treated cells resulted in caspase-8 activation and loss of mitochondrial membrane potential. Furthermore, inhibitors of caspase-3, -8 and -9 reduced the accelerative effect of PI 3-K inhibitors on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of PI 3-K inhibitors on TRAIL-mediated apoptosis may contribute to both the extrinsic and intrinsic pathways. Although PI 3-K inhibitors did not affect expression of the TRAIL receptors DR4 and DR5, we observed a marked reduction in expression of cellular FLICE-inhibitory protein (c-FLIP), Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1) and X-linked IAP (XIAP), whereas Bax was up-regulated and no significant difference was observed in expression of Bcl-xL, Bak or cIAP-2. Therefore, the PI 3-K/Akt signaling pathway provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of c-FLIP, Bcl-2, Bax, cIAP-1 and XIAP expression. These results suggest that PI 3-K inhibitors may represent a novel strategy for overcoming resistance to TRAIL-mediated apoptosis in OSCC cells.


Asunto(s)
Apoptosis , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Fragmentación del ADN , Humanos , Ligandos , Potenciales de la Membrana , Mitocondrias/patología , Neoplasias de la Boca/patología , Fosfatidilinositol 3-Quinasas/metabolismo
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