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Research Paper
Analysis of Apoptosome Dysregulation in Pancreatic Cancer and of its Role in Chemoresistance
Marco Corvaro, Claudia Fuoco, Martin Wagner and Francesco Cecconi
volume 6 | issue 2
February 2007Pages: 209 - 217
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The apoptosome is a multiprotein complex mediating the mithochondrial pathway of cell death. Its importance during development has been clearly demonstrated by knocking out key genes in mouse. APAF1 is the core protein of the apoptosome and its dosage is also critical in various cancer types, i.e. melanoma, germ line tumor, gastrointestinal cancer and B-type chronic lymphocytic leukemia. This is generally due to inactivation of the APAF1 locus by epigenetic phenomena or by activity of promoter regulators. We investigated the putative roles of the apoptosome in pancreatic ductal adenocarcinoma (PDAC). We found that both APAF1 mRNA and protein are dysregulated in human PDAC samples. Similarly, several PDAC cell lines exhibited variable levels of both APAF1 protein and mRNA. The response to cell death induction and its biochemical features were assessed by treatment of each line with commonly used chemotherapeutic agents. We found that the apoptosome pathway was not functional in most cell lines upon cytochrome c release from mitochondria. In addition, we restored APAF1 and Caspase-9 dosage in Panc-1 cells, where the apoptosome is downregulated, by overexpressing the murine cDNA of the two molecules, and we improved the death response to chemotherapeutic agents.
Authors
Marco Corvaro
University of Tor Vergata, Rome, Italy
Claudia Fuoco
University of Tor Vergata, Rome, Italy
Martin Wagner
University of Ulm, Germany
Francesco Cecconi
Dulbecco Telethon Institute, Rome, Italy
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.