Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer. Issue 1 (10th December 2004)

• Record Type: Journal Article
• Authors: Stoll, V; Calleja, V; Vassaux, G; Downward, J; Lemoine, N R
• Is Part Of: Gut. Volume 54:Issue 1(2005)
• Page Start: 109
• Page End: 116
• Publication Date: 2004-12-10
• Subjects: PI3K, phosphatidylinositol 3-kinase -- DMEM, Dulbecco's modified Eagle's medium -- FCS, fetal calf serum -- PFU, plaque forming units -- MOI, multiplicity of infection -- MTS, 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H -- EGF, epidermal growth factor -- BSA, bovine serum albumin -- PBS, phosphate buffered saline; pancreatic cancer -- ras oncogene -- gene therapy; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2004.046706
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: Ras signalling is frequently aberrant in pancreatic cancer so that there is constitutive activation of the phosphatidylinositol 3-kinase (PI3K) and AKT/protein kinase B pathway, as well as the RAF/MEK/ERK pathway. Aims: In the present study we investigated the role of the PI3K/AKT pathway in malignant transformation of pancreatic cancer cells. Methods: A genetic approach was used to interfere with signal transduction in vitro and in vivo. RASN17, a dominant negative mutant of RAS, was applied to inhibit the PI3K/AKT pathway upstream of PI3K. The regulatory p85β subunit of PI3K and the negative regulator PTEN were utilised to inhibit the pathway at the level of PI3K, and AAA-AKT, a dominant negative mutant of AKT was employed to interfere with PI3K/AKT signalling at the level of AKT. Results: Antiproliferative, proapoptotic, and anticancer effects were documented, showing that inhibition of the PI3K pathway in these cell lines suppresses tumour cell growth in vitro and reduces growth in nude mice. Conclusions: The PI3K/AKT pathway represents a potential therapeutic target for pancreatic cancer, and gene therapy may be one approach to produce selective inhibition.