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Baicalein, a widely used Chinese herbal medicine, has multiple pharmacological activities. However, the precise mechanisms of the anti-proliferation and anti-metastatic effects of baicalein on gallbladder cancer (GBC) remain poorly understood. Therefore, the aim of this study was to assess the anti-proliferation and anti-metastatic effects of baicalein and the related mechanism(s) on GBC. In the present study, we found that treatment with baicalein induced a significant inhibitory effect on proliferation and promoted apoptosis in GBC-SD and SGC996 cells, two widely used gallbladder cancer cell lines. Additionally, treatment with baicalein inhibited the metastasis of GBC cells. Moreover, we demonstrated for the first time that baicalein inhibited GBC cell growth and metastasis via down-regulation of the expression level of Zinc finger protein X-linked (ZFX). In conclusion, our studies suggest that baicalein may be a potential phytochemical flavonoid for therapeutics of GBC and ZFX may serve as a molecular marker or predictive target for GBC.
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Carcinoma/patología , Regulación hacia Abajo , Medicamentos Herbarios Chinos/farmacología , Flavanonas/farmacología , Neoplasias de la Vesícula Biliar/patología , Factores de Transcripción de Tipo Kruppel/genética , Animales , Apoptosis/efectos de los fármacos , Carcinoma/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Flavanonas/química , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Humanos , Masculino , Ratones Desnudos , Metástasis de la Neoplasia/prevención & control , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Ursolic acid (UA), a plant extract used in traditional Chinese medicine, exhibits potential anticancer effects in various human cancer cell lines in vitro. In the present study, we evaluated the anti-tumoral properties of UA against gallbladder carcinoma and investigated the potential mechanisms responsible for its effects on proliferation, cell cycle arrest and apoptosis in vitro. METHODS: The anti-tumor activity of UA against GBC-SD and SGC-996 cells was assessed using MTT and colony formation assays. An annexin V/PI double-staining assay was used to detect cell apoptosis. Cell cycle changes were detected using flow cytometry. Rhodamine 123 staining was used to assess the mitochondrial membrane potential (ΔΨm) and validate UA's ability to induce apoptosis in both cell lines. The effectiveness of UA in gallbladder cancer was further verified in vivo by establishing a xenograft GBC model in nude mice. Finally, the expression levels of cell cycle- and apoptosis-related proteins were analyzed by western blotting. RESULTS: Our results suggest that UA can significantly inhibit the growth of gallbladder cancer cells. MTT and colony formation assays indicated dose-dependent decreases in cell proliferation. S-phase arrest was observed in both cell lines after treatment with UA. Annexin V/PI staining suggested that UA induced both early and late phases of apoptosis. UA also decreased ΔΨm and altered the expression of molecules regulating the cell cycle and apoptosis. In vivo study showed intraperitoneally injection of UA can significantly inhibited the growth of xenograft tumor in nude mice and the inhibition efficiency is dose related. Activation of caspase-3,-9 and PARP indicated that mitochondrial pathways may be involved in UA-induced apoptosis. CONCLUSIONS: Taken together, these results suggest that UA exhibits significant anti-tumor effects by suppressing cell proliferation, promoting apoptosis and inducing 7cell cycle arrest both in vitro and in vivo. It may be a potential agent for treating gallbladder cancer.
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Bufalin, a major digoxin-like immunoreactive component of the Chinese medicine Chan Su, has been shown to exert a potential for anticancer activity against various human cancer cell lines in vitro. However, no detailed studies have so far been reported on its action on human gallbladder carcinoma cells. In this study, bufalin remarkably inhibited growth in human gallbladder cancer cells by decreasing cell proliferation, inducing cell cycle arrest and apoptosis in a dose-dependent manner. Bufalin also disrupted the mitochondrial membrane potential (ΔΨm) and regulated the expression of cell cycle and apoptosis regulatory molecules. Activation of caspase-9 and the subsequent activation of caspase-3 indicated that bufalin may be inducing mitochondria apoptosis pathways. Intraperitoneal injection of bufalin for 3 weeks significantly inhibited the growth of gallbladder carcinoma (GBC-SD) xenografts in athymic nude mice. Taken together, the results indicate that bufalin may be a potential agent for the treatment of gallbladder cancer.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bufanólidos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias de la Vesícula Biliar/patología , Animales , Western Blotting , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/metabolismo , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Gallbladder cancer is the most common malignant tumor of the biliary tract, and this condition has a rather dismal prognosis, with an extremely low five-year survival rate. To improve the outcome of unresectable and recurrent gallbladder cancer, it is necessary to develop new effective treatments and drugs. The purpose of the present study was to evaluate the effects of cordycepin on human gallbladder cells and uncover the molecular mechanisms responsible for these effects. The Cell Counting Kit-8 (CCK-8) and colony formation assays revealed that cordycepin affected the viability and proliferation of human gallbladder cancer cells in a dose- and time-dependent manner. Flow cytometric analysis showed that cordycepin induced S phase arrest in human gallbladder cancer cell lines(NOZ and GBC-SD cells). Cordycepin-induced apoptosis was observed using an Annexin V/propidium iodide (PI) double-staining assay, and the mitochondrial membrane potential (ΔΨm) decreased in a dose-dependent manner. Additionally, western blot analysis revealed the upregulation of cleaved-caspase-3, cleaved-caspase-9, cleaved-PARP and Bax and the downregulation of Bcl-2, cyclin A and Cdk-2 in cordycepin-treated cells. Moreover, cordycepin inhibited tumor growth in nude mice bearing NOZ tumors. Our results indicate that this drug may represent an effective treatment for gallbladder carcinoma.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Desoxiadenosinas/farmacología , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Animales , Antineoplásicos/química , Caspasa 3/genética , Caspasa 3/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxiadenosinas/química , Modelos Animales de Enfermedad , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Estructura Molecular , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayo de Tumor de Célula Madre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Gallbladder cancer, with high aggressivity and extremely poor prognosis, is the most common malignancy of the bile duct. The main objective of the paper was to investigate the effects of schisandrin B (Sch B) on gallbladder cancer cells and identify the mechanisms underlying its potential anticancer effects. We showed that Sch B inhibited the viability and proliferation of human gallbladder cancer cells in a dose-, time -dependent manner through MTT and colony formation assays, and decrease mitochondrial membrane potential (ΔΨm) at a dose-dependent manner through flow cytometry. Flow cytometry assays also revealed G0/G1 phase arrest and apoptosis in GBC-SD and NOZ cells. Western blot analysis of Sch B-treated cells revealed the upregulation of Bax, cleaved caspase-9, cleaved caspase-3, cleaved PARP and downregulation of Bcl-2, NF-κB, cyclin D1 and CDK-4. Moreover, this drug also inhibited the tumor growth in nude mice carrying subcutaneous NOZ tumor xenografts. These data demonstrated that Sch B induced apoptosis in gallbladder cancer cells by regulating apoptosis-related protein expression, and suggests that Sch B may be a promising drug for the treatment of gallbladder cancer.
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Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Lignanos/administración & dosificación , Compuestos Policíclicos/administración & dosificación , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclooctanos/administración & dosificación , Neoplasias de la Vesícula Biliar/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , FN-kappa B/biosíntesis , Proteínas de Neoplasias/biosíntesisRESUMEN
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA (lncRNA), is associated with metastasis and is an independent prognostic factor for lung cancer. Recent studies have demonstrated that MALAT1 plays an important role in other malignancies. However, little is known about the role of MALAT1 in gallbladder carcinoma (GBC), which is the most common cancer of the biliary tract and has an extremely poor prognosis. In this study, we focused on the expression, biological functions and mechanism of MALAT1 in GBC and found that MALAT1 was significantly upregulated in GBC tissues compared with corresponding non-cancerous tissues. Knockdown of MALAT1 in GBC cell lines using lentivirus-mediated RNA interference significantly inhibited the proliferation and metastasis of the GBC cells both in vitro and in vivo. Furthermore, ERK/MAPK pathway was found to be inactivated in the GBC cell lines after MALAT1 knockdown. These results indicated that MALAT1 might serve as an oncogenic lncRNA that promotes proliferation and metastasis of GBC and activates the ERK/MAPK pathway.
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Adenocarcinoma/secundario , Movimiento Celular , Proliferación Celular , Neoplasias de la Vesícula Biliar/patología , Sistema de Señalización de MAP Quinasas , ARN Largo no Codificante/fisiología , Adenocarcinoma/metabolismo , Línea Celular Tumoral , Femenino , Neoplasias de la Vesícula Biliar/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Baicalin, the main active ingredient in the Scutellaria baicalensis (SB), is prescribed for the treatment of various inflammatory diseases and tumors in clinics in China. In the present study, we evaluated the antitumor activity of baicalin for gallbladder carcinoma and the underlying mechanisms both in vitro and in vivo. Our results indicate that baicalin induced potent growth inhibition, cell cycle arrest, apoptosis and colony-formation inhibition in a dose-dependent manner in vitro. We observed inhibition of NF-κB nuclear translocation, up-regulation of Bax and down-regulation of Bcl-2, as well as increased caspase-3 and caspase-9 expression after baicalin treatment in vitro and in vivo, which indicates that the mitochondrial pathway was involved in baicalin-induced apoptosis. In addition, daily intraperitoneally injection of baicalin (15, 30 and 60 mg/kg) for 21 days significantly inhibited the growth of NOZ cells xenografts in nude mice, which improved the survival of baicalin-treated mice. In summary, baicalin exhibited a significant anti-tumor effect by suppressing cell proliferation, promoting apoptosis, and inducing cell cycle arrest in vitro, and by suppressing tumor growth and improving survival in vivo, which suggested that baicalin represents a novel therapeutic option for gallbladder carcinoma.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma/metabolismo , Flavonoides/farmacología , Neoplasias de la Vesícula Biliar/metabolismo , Mitocondrias/metabolismo , Animales , Antineoplásicos/uso terapéutico , Proteínas Reguladoras de la Apoptosis/metabolismo , Carcinoma/tratamiento farmacológico , Carcinoma/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina A/metabolismo , Ciclina B1/metabolismo , Ciclina D1/metabolismo , Flavonoides/uso terapéutico , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/patología , Xenoinjertos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Desnudos , Necrosis , Transducción de SeñalRESUMEN
Gallbladder carcinoma is the most common malignancy of the biliary tract, with a very low 5-year survival rate and extremely poor prognosis. Thus, new effective treatments and drugs are urgently needed for the treatment of this malignancy. In this study, for the first time we investigated the effects of triptolide on gallbladder cancer cells and identified the mechanisms underlying its potential anticancer effects. The MTT assay showed that triptolide decreased cell viability in a dose- and time-dependent manner. The results of the colony formation assay indicated that triptolide strongly suppressed colony formation ability in GBC-SD and SGC-996 cells. Flow cytometric analysis revealed that triptolide induced S phase arrest in gallbladder cancer cells. In addition, triptolide induced apoptosis, as shown by the results of annexin V/propidium iodide double-staining and Hoechst 33342 staining. Furthermore, triptolide decreased mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Finally, western blot analysis of triptolide-treated cells revealed the activation of caspase-3, caspase-9, PARP, and Bcl-2; this result demonstrated that triptolide induced apoptosis in gallbladder cancer cells by regulating apoptosis-related protein expression, and suggests that triptolide may be a promising drug to treat gallbladder carcinoma.
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Apoptosis/efectos de los fármacos , Diterpenos/química , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Fenantrenos/química , Fase S/efectos de los fármacos , Caspasa 3/biosíntesis , Caspasa 9/biosíntesis , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Diterpenos/administración & dosificación , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/química , Neoplasias de la Vesícula Biliar/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Fenantrenos/administración & dosificación , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesisRESUMEN
OBJECTIVE: To evaluate the effect of preoperative transarterial chemoembolization (TACE) on hepatocellular carcinoma located in caudate lobe. METHODS: Totally 29 cases of caudate lobe hepatocellular carcinoma admitted from January 2001 to December 2010 were analyzed retrospectively. Among the 29 patients, 23 were male and the other 6 were female. The median age was 52 years. According to receiving preoperative TACE or not, the 29 cases were divided into two groups: preoperative TACE plus surgery (group A, n = 11) and surgery only (group B, n = 18). The surgical results and long-term survival were compared between two groups. RESULTS: After TACE, the diameter of the tumour reduced by over 33.3% in 3 patients, 10.0% to 33.3% in 6 patients, and less than 10.0% in 2 patients. The duration of surgery and intraoperative blood loss in group A were (298 ± 39) minutes and (1031 ± 310) ml, respectively. The duration of surgery and intraoperative blood loss in group B were (281 ± 54) minutes and (868 ± 403) ml, respectively. No significant difference was found in terms of these two groups (t = 1.006, P = 0.324; t = 1.223, P = 0.232). In addition, 6 cases in group A developed complications and 4 cases in group B did so. Only one patient died because of postoperative complication, and this patient belonged to group A. No significant difference was found between two groups (χ(2) = 0.028, P = 0.868; χ(2) = 0.633, P = 0.426). The 5-year survival rate was 56.8% in group A and 34.9% in group B. The difference did not reach significant difference (P = 0.132). CONCLUSIONS: For hepatocellular carcinoma located in caudate lobe, preoperative TACE does not significantly increase the surgical difficulty and impair the safety. In addition, preoperative TACE has the tendency to provide benefit to long-term survival.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Carcinoma Hepatocelular/cirugía , Hepatectomía , Humanos , Neoplasias Hepáticas/cirugía , Estudios RetrospectivosRESUMEN
AIM: To assess whole-body fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the management of small bowel obstructions (SBOs) secondary to gastric cancer and its role in treatment strategies. METHODS: The medical records of all of the patients who were admitted for an intestinal obstruction after curative resection for gastric cancer were retrospectively reviewed. PET/CT was performed before a clinical treatment strategy was established for each patient. The patients were divided into 2 groups: patients with no evidence of a tumor recurrence and patients with evidence of a tumor recurrence. Tumor recurrences included a local recurrence, peritoneal carcinomatosis or distant metastases. The primary endpoint was the 1-year survival rate, and other variables included patient demographics, the length of hospital stay, complications, and mortality. RESULTS: The median time between a diagnosis of gastric cancer and the detection of a SBO was 1.4 years. Overall, 31 of 65 patients (47.7%) had evidence of a tumor recurrence on the PET/CT scan, which was the only factor that was associated with poor survival. Open and close surgery was the main type of surgical procedure reported for the patients with tumor recurrences. R0 resections were performed in 2 patients, including 1 who underwent combined adjacent organ resection. In the group with no evidence of a tumor recurrence on PET/CT, bowel resections were performed in 7 patients, adhesiolysis was performed in 7 patients, and a bypass was performed in 1 patient. The 1-year survival curves according to PET/CT evidence of a tumor recurrence vs no PET/CT evidence of a tumor recurrence were significantly different, and the 1-year survival rates were 8.8% vs 93.5%, respectively. There were no significant differences (P = 0.71) in the 1-year survival rates based on surgical vs nonsurgical management (0% with nonoperative treatment vs 20% after exploratory laparotomy). CONCLUSION: (18)F-FDG PET/CT can be used to identify the causes of bowel obstructions in patients with a history of gastric cancer, and this method is useful for planning the surgical management of these patients.
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Obstrucción Intestinal/cirugía , Neoplasias Gástricas/cirugía , Anciano , Femenino , Fluorodesoxiglucosa F18 , Humanos , Obstrucción Intestinal/diagnóstico , Obstrucción Intestinal/etiología , Obstrucción Intestinal/mortalidad , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Análisis Multivariante , Recurrencia Local de Neoplasia , Selección de Paciente , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Radiofármacos , Reoperación , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/secundario , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Gallbladder carcinoma is a malignant tumor with a very low 5-year survival rate because of the difficulty with its early diagnosis and the very poor prognosis of the advanced cancer state. The aims of this study were to determine whether curcumin could induce the apoptosis of a gallbladder carcinoma cell line, GBC-SD, and to clarify its related mechanism. METHODS: First, the anti-proliferative activities of curcumin-treated and untreated GBC-SD cells were determined using the MTT and colony formation assays. Then, the early apoptosis of cells was detected by the annexin V/propidium iodide double-staining assay and Hoechst 33342 staining assay. Detection of mitochondrial membrane potential was used to validate the ability of curcumin on inducing apoptosis in GBC-SD cells. Cell cycle changes were detected by flow cytometric analysis. Finally, the expressions of the apoptosis-related proteins or genes caspase-3, PARP, Bcl-2, and Bax were analyzed by western blot and quantitative real time PCR assay. Statistical analyses were performed using the Student's t-test for comparison of the results obtained from cells with or without curcumin treatment. RESULTS: The MTT assay revealed that curcumin had induced a dose- and a time-dependent decrease in cell viability. Colony counting indicated that curcumin had induced a dose-dependent decrease in the colony formation ability in GBC-SD cells. Cells treated with curcumin were arrested at the S phase, according to the flow cytometric analysis. A significant induction of both the early and late phases of apoptosis was shown by the annexin V-FITC and PI staining. Morphological changes in apoptotic cells were also found by the Hoechst 33342 staining. After treatment with curcumin fluorescence shifted from red to green as ΔΨm decreased. Furthermore, western blot and quantitative real time PCR assays demonstrated that the curcumin induced apoptosis in GBC-SD cells by regulating the ratio of Bcl-2/Bax and activating the expression of cleaved caspase-3. CONCLUSIONS: Taken together, the results indicate that curcumin may be a potential agent for the treatment of gallbladder cancer.
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MicroRNAs are negative regulators of mRNA, and latest studies show that "mRNAs can also inhibit microRNAs". With these reciprocal interactions, different mRNAs with identical "microRNA binding site" cim regulate each other by competitively binding to the same microRNA pool. This is the novel competing endogenous RNA (ceRN A)regulating mechanism. The ceRN A mechanism, which is a totally new regulating mechanism , greatly expands the regulatory network across genes. It has been proved by experimental evidence that, in HCT116 colon cancer cells,KRAS and PTEN , ZEB2 and PTEN can regulate each other by ceRNA mechanism.
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Neoplasias Colorrectales/genética , MicroARNs/genética , Células HCT116 , Humanos , Fosfohidrolasa PTEN , ARN MensajeroRESUMEN
Formation of neural circuits depends on stable contacts between neuronal processes, mediated by interaction of cell adhesion molecules, including N-cadherin. In the present study, we found that activity-dependent dendrite arborization specifically requires N-cadherin-mediated extracellular neuron-neuron interaction, because the enhancement did not occur for neurons cultured in isolation or plated on an astrocyte monolayer and was abolished by a recombinant soluble N-cadherin ectodomain. Furthermore, depolarization elevated the level of membrane-associated cadherin/catenin complexes and surface N-cadherin. Importantly, surface N-cadherin elevation is specifically required for the maintenance of nascent dendrite arbors. Through loss- and gain-of-function approaches, we showed that N-cadherin-mediated dendrite growth requires association of the cadherin/catenin complex with the actin cytoskeleton. In summary, these results identify a previously unexplored and specific function for activity-induced, N-cadherin-mediated neuron-neuron contacts in the maintenance of dendrite arbors.
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Cadherinas/metabolismo , Comunicación Celular , Dendritas/metabolismo , Neuronas/citología , Neuronas/metabolismo , Actinas/metabolismo , Animales , Cateninas/metabolismo , Adhesión Celular , Células Cultivadas , Unión Proteica , Ratas , Ratas Sprague-DawleyRESUMEN
Neural circuit development requires concurrent morphological and functional changes. Here, we identify coordinated and inversely correlated changes in dendritic morphology and mEPSC amplitude following increased neural activity. We show that overexpression of beta-catenin, a molecule that increases total dendritic length, mimics the effects of increased neuronal activity by scaling down mEPSC amplitudes, while postsynaptic expression of a protein that sequesters beta-catenin reverses the effects of activity on reducing mEPSC amplitudes. These results were confirmed immunocytochemically as changes in the size and density of surface synaptic AMPA receptor clusters. In individual neurons there was an inverse linear relationship between total dendritic length and average mEPSC amplitude. Importantly, beta-catenin overexpression in vivo promoted dendritic growth and reduced mEPSC amplitudes. Together, these results demonstrate that coordinated changes in dendritic morphology and unitary excitatory synaptic strength may serve as an important intrinsic mechanism that helps prevent neurons from overexcitation during neural circuit development.