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Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer

¹ Cancer Research UK Molecular Oncology Unit, Faculty of Medicine, Imperial College London, London, UK
² Cancer Research UK Molecular Oncology Unit, Faculty of Medicine, Imperial College London, London, UK, and Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, UK
³ Signal Transduction Laboratory, Cancer Research UK London Research Institute, London UK

Correspondence to:
Correspondence to:
Professor N R Lemoine
Cancer Research UK Clinical Centre, Barts and The London School of Medicine, Queen Mary’s University of London, Charterhouse Square, London EC1M 6BQ, UK; nick.lemoine{at}cancer.org.uk

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 p85ß 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.

Abbreviations: 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

Keywords: pancreatic cancer; ras oncogene; gene therapy

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