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1.
Angiogenesis ; 16(4): 903-17, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23838996

RESUMEN

Hypoxia-inducible factors (HIFs) and STAT-3 play essential roles in angiogenesis. HIF-1α and STAT-3 are clients of the heat shock protein 90 (HSP90). We hypothesized that ganetespib, a potent HSP90 inhibitor, would disrupt angiogenesis in colorectal cancer (CRC) through inhibition of HIF-1α and STAT-3. CRC cell lines (HCT116 and HT29) were used in all the experiments. Egg CAM and HUVEC assays revealed decreased angiogenesis in ganetespib treated cell lines. Ganetespib inhibited matrigel plug vascularization and tumor growth of xenografts. Significant inhibition of PDGFA, FGF2, Ang-1, Ang-2, TGFß1, VEGF, HIF-1α and STAT-3 expression was observed in both cell lines treated ganetespib. HIF-1α overexpression resulted in the increase VEGF and STAT-3 expression and this was inhibited by ganetespib. HIF-1α knockdown inhibited VEGF and STAT-3 expression. STAT-3 knockdown inhibited VEGF but not HIF-1α expression. HSP90, STAT-3 and VEGF expression was significantly higher in CRC compared to adjacent normal tissue. Significant downregulation of PDGFA, FGF2, Ang-1, Ang-2, TGFß1, VEGF, STAT-3 and HIF-1α mRNA was observed in the post ganetespib treatment tumor samples from patients with rectal cancer. These results collectively suggest that inhibition of HSP90 is a promising antiangiogenic strategy in CRC. HSP90 angiogenic effects are mediated through HIF-1α and STAT-3.


Asunto(s)
Adenocarcinoma/irrigación sanguínea , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Neoplasias Colorrectales/irrigación sanguínea , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Factor de Transcripción STAT3/antagonistas & inhibidores , Triazoles/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Colágeno , Neoplasias Colorrectales/patología , Regulación hacia Abajo , Combinación de Medicamentos , Femenino , Factor 2 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Factor 2 de Crecimiento de Fibroblastos/biosíntesis , Factor 2 de Crecimiento de Fibroblastos/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Proteínas HSP90 de Choque Térmico/fisiología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Laminina , Ratones Desnudos , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Factor de Crecimiento Derivado de Plaquetas/genética , Proteoglicanos , ARN Mensajero/biosíntesis , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/genética , Neoplasias del Recto/patología , Ribonucleasa Pancreática/antagonistas & inhibidores , Ribonucleasa Pancreática/biosíntesis , Ribonucleasa Pancreática/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/fisiología , Organismos Libres de Patógenos Específicos , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/biosíntesis , Factor de Crecimiento Transformador beta1/genética , Triazoles/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genética , Proteínas de Transporte Vesicular/antagonistas & inhibidores , Proteínas de Transporte Vesicular/biosíntesis , Proteínas de Transporte Vesicular/genética
2.
PLoS One ; 7(11): e51126, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23226477

RESUMEN

Enkephalins play a major role in reproductive physiology in crustaceans; however their role in reproductive development in insects is largely unknown. We investigated the effect of exposure to exogenous leucine-enkephalin (Leu-Enk), methionine-enkephalin (Met-Enk), and the opioid antagonist naloxone on gonad development in the Eastern lubber grasshopper, Romalea microptera. Injection of either Leu-Enk or naloxone alone significantly increased the testicular index and testicular follicular diameter in males, and the ovarian index, oocyte length, and oocyte diameter in females. In contrast, injection of Met-Enk inhibited all measures of reproductive development in both sexes. Surprisingly, co-injection of naloxone with either enkephalin enhanced the effect associated with administration of the enkephalin alone. This study clearly demonstrates the ability of enkephalins to disrupt insect sexual development and also suggests the existence of conserved enkephaline-dependent regulatory mechanisms in insects and crustaceans.


Asunto(s)
Encefalinas/farmacología , Saltamontes/efectos de los fármacos , Saltamontes/crecimiento & desarrollo , Animales , Encefalina Leucina/farmacología , Encefalina Metionina/farmacología , Femenino , Masculino , Naloxona/farmacología , Oocitos/efectos de los fármacos , Ovario/efectos de los fármacos , Ovario/crecimiento & desarrollo , Reproducción/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/crecimiento & desarrollo
3.
Biochem Biophys Res Commun ; 417(2): 874-9, 2012 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-22206672

RESUMEN

Dynamic cell interaction with ECM components has profound influence in cancer progression. SPARC is a component of the ECM, impairs the proliferation of different cell types and modulates tumor cell aggressive features. We previously reported that SPARC expression significantly impairs medulloblastoma tumor growth in vivo. In this study, we demonstrate that expression of SPARC inhibits medulloblastoma cell proliferation. MTT assay indicated a dose-dependent reduction in tumor cell proliferation in adenoviral mediated expression of SPARC full length cDNA (Ad-DsRed-SP) in D425 and UW228 cells. Flow cytometric analysis showed that Ad-DsRed-SP-infected cells accumulate in the G2/M phase of cell cycle. Further, immunoblot and immunoprecipitation analyses revealed that SPARC induced G2/M cell cycle arrest was mediated through inhibition of the Cyclin-B-regulated signaling pathway involving p21 and Cdc2 expression. Additionally, expression of SPARC decreased STAT3 phosphorylation at Tyr-705; constitutively active STAT3 expression reversed SPARC induced G2/M arrest. Ad-DsRed-SP significantly inhibited the pre-established orthotopic tumor growth and tumor volume in nude-mice. Immunohistochemical analysis of tumor sections from mice treated with Ad-DsRed-SP showed decreased immunoreactivity for pSTAT3 and increased immunoreactivity for p21 compared to tumor section from mice treated with mock and Ad-DsRed. Taken together our studies further reveal that STAT3 plays a key role in SPARC induced G2/M arrest in medulloblastoma cells. These new findings provide a molecular basis for the mechanistic understanding of the effects of SPARC on medulloblastoma tumor cell proliferation.


Asunto(s)
Puntos de Control del Ciclo Celular , Neoplasias Cerebelosas/patología , Meduloblastoma/patología , Osteonectina/biosíntesis , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Humanos , Ratones , Osteonectina/genética , Factor de Transcripción STAT3/genética , Ensayos Antitumor por Modelo de Xenoinjerto
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