RESUMEN
TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically, and here we examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73, respectively). The acidic transactivation-domain-bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the ΔN isoforms (lacking the acidic transactivation domain) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-suppressive functions. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway. Here we show that deletion of the ΔN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the ß cells of the pancreas. We found that IAPP is causally involved in this tumour regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes, caused rapid tumour regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.
Asunto(s)
Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Linfoma/metabolismo , Linfoma/patología , Proteína p53 Supresora de Tumor/deficiencia , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Genes Supresores de Tumor , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Linfoma/tratamiento farmacológico , Linfoma/genética , Masculino , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteína 3 Modificadora de la Actividad de Receptores/metabolismo , Receptores de Calcitonina/metabolismo , Timo/metabolismo , Timo/patología , Transactivadores/genética , Transactivadores/metabolismo , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
OBJECTIVE: To determine the influence of early pain relief for patients with suspected appendicitis on the diagnostic performance of surgical residents. METHODS: A prospective randomized, double-blind, placebo-controlled trial was conducted for patients with suspected appendicitis. The patients were randomized to receive placebo (normal saline intravenous [IV]) infusions over 5 minutes or the study drug (morphine 5 mg IV). All of the clinical evaluations by surgical residents were performed 30 minutes after administration of the study drug or placebo. After obtaining the clinical probability of appendicitis, as determined by the surgical residents, abdominal computed tomography was performed. The primary objective was to compare the influence of IV morphine on the ability of surgical residents to diagnose appendicitis. RESULTS: A total of 213 patients with suspected appendicitis were enrolled. Of these patients, 107 patients received morphine, and 106 patients received placebo saline. The negative appendectomy percentages in each group were similar (3.8% in the placebo group and 3.2% in the pain control group, p=0.62). The perforation rates in each group were also similar (18.9% in the placebo group and 14.3% in the pain control group, p=0.75). Receiver operating characteristic analysis revealed that the overall diagnostic accuracy in each group was similar (the area under the curve of the placebo group and the pain control group was 0.63 v. 0.61, respectively, p=0.81). CONCLUSIONS: Early pain control in patients with suspected appendicitis does not affect the diagnostic performance of surgical residents.