RESUMEN
AIMS/HYPOTHESIS: The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells. METHODS: We measured circulating and psoriatic plaque iNKT cell numbers in two patients with type 2 diabetes and psoriasis before and after commencing GLP-1 analogue therapy. In addition, we investigated the in vitro effects of GLP-1 on iNKT cells and looked for a functional GLP-1 receptor on these cells. RESULTS: The Psoriasis Area and Severity Index improved in both patients following 6 weeks of GLP-1 analogue therapy. This was associated with an alteration in iNKT cell number, with an increased number in the circulation and a decreased number in psoriatic plaques. The GLP-1 receptor was expressed on iNKT cells, and GLP-1 induced a dose-dependent inhibition of iNKT cell cytokine secretion, but not cytolytic degranulation in vitro. CONCLUSIONS/INTERPRETATION: The clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/metabolismo , Células T Asesinas Naturales/metabolismo , Psoriasis/complicaciones , Psoriasis/tratamiento farmacológico , Receptores de Glucagón/metabolismo , Recuento de Células , Línea Celular , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Péptido 1 Similar al Glucagón/efectos adversos , Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Liraglutida , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/inmunología , Obesidad/complicaciones , Psoriasis/inmunología , Psoriasis/metabolismo , ARN Mensajero/metabolismo , Receptores de Glucagón/agonistas , Receptores de Glucagón/genética , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Piel/efectos de los fármacos , Piel/inmunología , Piel/patologíaRESUMEN
Despite the established role of insulin-like growth factor binding protein-3 (IGFBP-3) as a growth inhibitor in vitro, a high level of IGFBP-3 in breast tumor tissue is associated with the stimulation of xenograft growth in mice and poor prognosis in patients. To understand the contribution of IGFBP-3 to breast cancer progression, tandem affinity purification was used to identify novel interacting proteins. The endoplasmic reticulum protein, glucose-regulated protein 78 (GRP78), was shown to bind to IGFBP-3, confirmed by colocalization, coimmunoprecipitations, glutathione S-transferase (GST) pulldowns and a nanomolar binding affinity. GST pulldowns also indicated that the GRP78 ATPase domain mediated the interaction with IGFBP-3. The critical roles of GRP78 in the unfolded protein response and macroautophagy led to an investigation of possible links between IGFBP-3, GRP78 and cellular stress responses. IGFBP-3 was found to stimulate the survival of breast cancer cells subjected to glucose starvation and hypoxia. Pharmacological inhibitors and small interfering RNA knockdown established that the increased survival of IGFBP-3-expressing cells was dependent on an intact autophagy response, as well as GRP78. The contribution of autophagy was confirmed by the demonstration that IGFBP-3 expression increases both the formation of autophagic puncta and flux through the system. In conclusion, we have shown that IGFBP-3 stimulates autophagy and thereby promotes the survival of breast cancer cells exposed to conditions that represent the adverse microenvironments encountered by solid tumor cells in vivo.
Asunto(s)
Neoplasias de la Mama/patología , Proteínas de Choque Térmico/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Animales , Autofagia/fisiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Chaperón BiP del Retículo Endoplásmico , Femenino , Células HEK293 , Proteínas de Choque Térmico/genética , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Células MCF-7 , Transducción de Señal , Análisis de Supervivencia , Microambiente TumoralRESUMEN
LIM-only protein 4 (LMO4) is strongly linked to the progression of breast cancer. Although the mechanisms underlying this phenomenon are not well understood, a role is emerging for LMO4 in regulation of the cell cycle. We determined the solution structure of LMO4 in complex with CtIP (C-terminal binding protein interacting protein)/RBBP8, a tumour suppressor protein that is involved in cell cycle progression, DNA repair and transcriptional regulation. Our data reveal that CtIP and the essential LMO cofactor LDB1 (LIM-domain binding protein 1) bind to the same face on LMO4 and cannot simultaneously bind to LMO4. We hypothesise that overexpression of LMO4 may disrupt some of the normal tumour suppressor activities of CtIP, thereby contributing to breast cancer progression.