The ubiquitin-proteasome pathway mediates the downregulation of gelsolin protein levels in pancreati
June 29th, 2008 | by admin |The ubiquitin-proteasome pathway mediates the downregulation of gelsolin protein levels in pancreatic cancer.
One of the oldest observations in cancer biology is that transformed cells display a disturbed cytoskeleton. The underlying mechanisms, however, remain only partly understood. In an effort to identify possible mechanisms, we contrast the proteome of pancreatic cancer to matched normal pancreas and we observe diminished protein levels of gelsolin - an actin filament severing and capping protein of crucial importance for maintaining cytoskeletal integrity - in pancreatic cancer. Furthermore, pancreatic ductal adenocarcinomas display substantially decreased levels of gelsolin as judged by Western blot and immunohistochemical analyses of tissue micoarrays, when cancerous and untransformed tissue of the same patients are compared (P<0.05). Importantly no marked down regulation of gelsolin mRNA is observed (P>0.05), suggesting that post-transcriptional mechanisms mediate low gelsolin protein levels. In apparent agreement, high activity ubiquitin-proteasome pathway in both patient samples and the BxPC-3 pancreatic cancer cell line is detected and inhibition of the 26s proteasome system quickly restores gelsolin protein levels in the latter cell line. The status of ubiquitinated gelsolin is related with lymph node metastasis of pancreatic cancer. We conclude that in pancreatic cancer gelsolin levels are actively down regulated and that enhanced targeting of gelsolin to the ubiquitin-proteasome pathway is an important contributing factor to this effect.
Ni XG, Zhou L, Wang GQ, Liu SM, Bai XF, Liu F, Peppelenbosch MP, Zhao P.
Department of Endoscopy.