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 p85beta 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.
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 p85beta 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.
Authors: Victor M Bondar; Bridget Sweeney-Gotsch; Michael Andreeff; Gordon B Mills; David J McConkey Journal: Mol Cancer Ther Date: 2002-10 Impact factor: 6.261
Authors: John P Neoptolemos; Deborah D Stocken; Helmut Friess; Claudio Bassi; Janet A Dunn; Helen Hickey; Hans Beger; Laureano Fernandez-Cruz; Christos Dervenis; François Lacaine; Massimo Falconi; Paolo Pederzoli; Akos Pap; David Spooner; David J Kerr; Markus W Büchler Journal: N Engl J Med Date: 2004-03-18 Impact factor: 91.245
Authors: Haiwen Ni; Fazal Shirazi; Veerabhadran Baladandayuthapani; Heather Lin; Isere Kuiatse; Hua Wang; Richard J Jones; Zuzana Berkova; Yasumichi Hitoshi; Stephen M Ansell; Steven P Treon; Sheeba K Thomas; Hans C Lee; Zhiqiang Wang; R Eric Davis; Robert Z Orlowski Journal: Clin Cancer Res Date: 2018-08-20 Impact factor: 12.531