RESUMEN
Methionine adenosyltransferase (MAT) is an essential enzyme that is responsible for the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines. MAT1A is expressed in normal liver and MAT2A is expressed in all extrahepatic tissues. MAT2A expression is increased in human colon cancer and in colon cancer cells treated with mitogens, whereas silencing MAT2A resulted in apoptosis. The aim of the current work was to examine the mechanism responsible for MAT2A-dependent growth and apoptosis. We found that in RKO (human adenocarcinoma cell line) cells, MAT2A siRNA treatment lowered cellular SAMe and putrescine levels by 70-75%, increased apoptosis and inhibited growth. Putrescine supplementation blunted significantly MAT2A siRNA-induced apoptosis and growth suppression. Putrescine treatment (100pmol/L) raised MAT2A mRNA level to 4.3-fold of control, increased the expression of c-Jun and c-Fos and binding to an AP-1 site in the human MAT2A promoter and the promoter activity. In human colon cancer specimens, the expression levels of MAT2A, ornithine decarboxylase (ODC), c-Jun and c-Fos are all elevated as compared to adjacent non-tumorous tissues. Overexpression of ODC in RKO cells also raised MAT2A mRNA level and MAT2A promoter activity. ODC and MAT2A are also overexpressed in liver cancer and consistently, similar MAT2A-ODC-putrescine interactions and effects on growth and apoptosis were observed in HepG2 cells. In conclusion, there is a crosstalk between polyamines and MAT2A. Increased MAT2A expression provides more SAMe for polyamines biosynthesis; increased polyamine (putrescine in this case) can activate MAT2A at the transcriptional level. This along with increased ODC expression in cancer all feed forward to further enhance the proliferative capacity of the cancer cell.
Asunto(s)
Neoplasias del Colon/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina Adenosiltransferasa/metabolismo , Putrescina/metabolismo , Anciano , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/enzimología , Femenino , Humanos , Neoplasias Hepáticas/enzimología , Masculino , Metionina Adenosiltransferasa/genética , Persona de Mediana Edad , Ornitina Descarboxilasa/genética , Ornitina Descarboxilasa/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Interferente Pequeño , S-Adenosilmetionina/metabolismo , Factor de Transcripción AP-1/metabolismo , Transcripción GenéticaRESUMEN
We report an incident of complete stapled closure of the rectal lumen following stapled hemorrhoidopexy. A patient with symptomatic prolapsing hemorrhoids underwent a stapled hemorrhoidopexy as a day-case procedure. After application of the pursestring suture and firing of the dedicated stapler the rectal lumen was found to have been completely obliterated. Endoscopic assessment using a flexible sigmoidoscope confirmed the absence of a rectal lumen. The patient was woken up and a gastrograffin enema performed. Contrast was injected under high pressure into the rectal lumen and a small defect in the mid point of the staple line was revealed. A fine guidewire was passed and endoscopic balloon dilatation achieved. This complication could have had catastrophic consequences and potentially required major surgical intervention. Although unlikely to occur, we believe that surgeons should be aware of this possible problem and a radiologic/endoscopic approach should be considered before more aggressive surgical intervention is undertaken.