Abstract
A well-known observation with respect to 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 compared the proteome of pancreatic cancer with matched normal pancreas and observed diminished protein levels of gelsolin--an actin filament severing and capping protein of crucial importance for maintaining cytoskeletal integrity--in pancreatic cancer. Additionally, pancreatic ductal adenocarcinomas displayed substantially decreased levels of gelsolin as judged by Western blot and immunohistochemical analyses of tissue micoarrays, when compared with cancerous and untransformed tissue from the same patients (P < 0.05). Importantly, no marked downregulation of gelsolin mRNA was 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 was detected, and inhibition of the 26s proteasome system quickly restored gelsolin protein levels in the latter cell line. The status of ubiquitinated gelsolin is related to lymph node metastasis of pancreatic cancer. In conclusion, gelsolin levels are actively downregulated in pancreatic cancer and enhanced targeting of gelsolin to the ubiquitin-proteasome pathway is an important contributing factor for this effect.
Highlights
Pancreatic cancer is one of the most virulent malignances with an overall five-year survival rate of only 3–5% and a median survival time after diagnosis of < 6 months [1]
Patients and Specimens Fresh tissue samples of 11 pancreatic ductal adenocarcinomas and their corresponding distant normal counterparts were obtained at the time of resection with informed consent from Cancer Institute and Hospital (CIH), Chinese Academy of Medical Sciences (CAMS), and Peking Union Medical College (PUMC) between November 2001 and March 2003
Proteomic Chip Analysis In an effort to obtain insight into the molecular mechanisms that govern aberrant cytoskeletal structure in pancreatic cancer, we compared the holo-proteome ductal adenocarcinoma tissues showed extremely low or undetectable expressions of gelsolin compared with matched normal pancreatic tissues (P < 0.05)
Summary
Pancreatic cancer is one of the most virulent malignances with an overall five-year survival rate of only 3–5% and a median survival time after diagnosis of < 6 months [1] Despite this immense clinical problem, pancreatic cancer biology remains poorly understood in comparison with other cancers. It has been recognized for almost 40 years that transformed cells display a disturbed actin cytoskeletal structure, the mechanisms mediating disturbed actin filament organization in pancreatic cancer remain largely obscure. Gelsolin is an obvious candidate for explaining altered cytoskeletal reorganization in pancreatic cancer In support for such a notion, diminished expression
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