RESUMEN
BACKGROUND: Actin polymerisation is stimulated by the actin-related protein (ARP) 2/3 complex and drives cell migration. This complex is activated by Wiskott-Aldrich syndrome protein family (WASP) verprolin homologous protein (WAVE) proteins. WAVE1 and -3 have been implicated in the aggressiveness of metastatic prostate cancer cells. MATERIALS AND METHODS: Cell growth, motility and invasion were analyzed in WAVE1- and WAVE3-knockdown PC-3 cells along with the ARP2/3 inhibitor, CK-0944636. Confocal microscopy was adopted to examine protein co-localisation. Immunoprecipitation approaches were used to determine protein tyrosine phosphorylation. RESULTS: Cell growth suppression was observed with WAVE3 knockdown and ARP2/3 inhibition. Reduced cell invasion effects observed with WAVE1 knockdown appeared to be rescued by ARP2/3 inhibition. WAVE1 and WAVE3 and ARP2 co-localisation was lost in PC-3 WAVE-knockdown cells, while increased ARP2 tyrosine phosphorylation was observed with WAVE3 knockdown. CONCLUSION: These results implicate a contributory role of WAVE1 and -3 to the metastatic phenotype of PC-3 cells through their interaction with the ARP2/3 complex.
Asunto(s)
Citoesqueleto de Actina/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Actinas/metabolismo , Neoplasias de la Próstata/metabolismo , Familia de Proteínas del Síndrome de Wiskott-Aldrich/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/antagonistas & inhibidores , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Técnicas de Silenciamiento del Gen , Humanos , Indoles/farmacología , Masculino , Invasividad Neoplásica , Fenotipo , Fosforilación , Polimerizacion , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Unión Proteica , Interferencia de ARN , Transducción de Señal , Tiofenos/farmacología , Tirosina , Familia de Proteínas del Síndrome de Wiskott-Aldrich/genéticaRESUMEN
The CCN family of proteins comprises the members CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6. They share four evolutionarily conserved functional domains, and usually interact with various cytokines to elicit different biological functions including cell proliferation, adhesion, invasion, migration, embryonic development, angiogenesis, wound healing, fibrosis and inflammation through a variety of signalling pathways. In the past two decades, emerging functions for the CCN proteins (CCNs) have been identified in various types of cancer. Perturbed expression of CCNs has been observed in a variety of malignancies. The aberrant expression of certain CCNs is associated with disease progression and poor prognosis. Insight into the detailed mechanisms involved in CCN-mediated regulation may be useful in understanding their roles and functions in tumorigenesis and cancer metastasis. In this review, we briefly introduced the functions of CCNs, especially in cancer.
Asunto(s)
Proteínas CCN de Señalización Intercelular/genética , Factor de Crecimiento del Tejido Conjuntivo/genética , Proteína 61 Rica en Cisteína/genética , Neoplasias/genética , Proteína Hiperexpresada del Nefroblastoma/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Proteínas CCN de Señalización Intercelular/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Proteína 61 Rica en Cisteína/metabolismo , Humanos , Metástasis de la Neoplasia , Neoplasias/metabolismo , Neoplasias/patología , Proteína Hiperexpresada del Nefroblastoma/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismoRESUMEN
Triple-negative breast cancer (TNBC) is a subtype of poor prognosis, highly invasive and difficult-to-treat breast cancers accounting for approximately 15% of clinical cases. Given the poor outlook and lack of sustained response to conventional therapies, TNBC has been the subject of intense studies on new therapeutic approaches in recent years. The development of targeted cancer therapies, often in combination with established chemotherapy, has been applied to a number of new clinical studies in this setting in recent years. This review will highlight recent therapeutic advances in TNBC, focusing on small-molecule drugs and their associated biological mechanisms of action, and offering the possibility of improved prospects for this patient group in the near future.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Humanos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
A major factor controlling the metastatic nature of cancer cells is their motility. Alterations in the signalling pathways controlling its regulation can lead to tumor cell invasion and metastasis. Directional motility involves protrusion of the cell's leading edge, via formation of filopodia and lamellipodia, adhesion to the substrate followed by tail retraction and de-adhesion. Rho GTPase binding proteins function as activators of the actin cytoskeleton and are key players in the transendothelial migration of cancer cells. Activation of the specific GTPases Rho, Rac1 and Cdc42 results in formation of actin stress fibres, membrane ruffles, lamellipodia and filopodia respectively and in cortical actin assembly. Pathways through which Rho GTPases elicit these effects are through direct interaction with members of the Wiskott-Alrich Syndrome Protein (WASP) family which stimulates structures such as lamellipodia and filopodia. The present review explores the role and function of Rho GTPases, WASP and WAVE in cancer metastasis.
Asunto(s)
Neoplasias/metabolismo , Transducción de Señal , Familia de Proteínas del Síndrome de Wiskott-Aldrich/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Animales , Movimiento Celular/genética , Susceptibilidad a Enfermedades , Humanos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Unión Proteica , Familia de Proteínas del Síndrome de Wiskott-Aldrich/antagonistas & inhibidores , Familia de Proteínas del Síndrome de Wiskott-Aldrich/química , Familia de Proteínas del Síndrome de Wiskott-Aldrich/genética , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismo , Proteínas de Unión al GTP rho/genéticaRESUMEN
BACKGROUND: WAVE2 plays a crucial role in actin polymerisation and cell migration. We aimed to investigate the expression and cellular functions of WAVE2 in human gastric cancer (GC). MATERIALS AND METHODS: The level of WAVE2 was determined using quantitative PCR (Q-PCR) in a cohort of human gastric tissues. Expression of WAVE2, ARP2, NWASP, ROCK1 and ROCK2 was examined using RT-PCR in paired tissues. WAVE2 and ARP2 protein co-expression was examined. Anti-WAVE2 transgene ribozymes were constructed and transiently transfected into human GC cells. RESULTS: Down-regulation of WAVE2 expression in GC was significantly correlated with lymph node metastasis. WAVE2 was positively correlated with E-cadherin and negatively with TWIST. Immunohistochemically, WAVE2 and ARP2 were not co-expressed in serial mirror sections. In vitro, WAVE2 knockdown was shown to increase cell motility, whilst ROCK inhibitor treatment reduced this effect in HGC27 cells. CONCLUSION: WAVE2 is down-regulated in GC and loses its metastatic role in GC. Knockdown of WAVE2 could increase metastatic potential by promoting the growth, invasiveness, motility, adhesiveness and suppressing EMT (epithelial-mesenchymal transition) of GC cells.