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    Key role of phosphoinositide 3-kinase class IB in pancreatic cancer

    Access Status
    Open access via publisher
    Authors
    Edling, C.
    Selvaggi, F.
    Buus, R.
    Maffucci, T.
    Di Sebastiano, P.
    Friess, H.
    Innocenti, P.
    Kocher, H.
    Falasca, Marco
    Date
    2010
    Type
    Journal Article
    
    Metadata
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    Citation
    Edling, C. and Selvaggi, F. and Buus, R. and Maffucci, T. and Di Sebastiano, P. and Friess, H. and Innocenti, P. et al. 2010. Key role of phosphoinositide 3-kinase class IB in pancreatic cancer. Clinical Cancer Research. 16 (20): pp. 4928-4937.
    Source Title
    Clinical Cancer Research
    DOI
    10.1158/1078-0432.CCR-10-1210
    ISSN
    1078-0432
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/20327
    Collection
    • Curtin Research Publications
    Abstract

    Purpose: Phosphoinositide 3-kinase (PI3K) signaling is well established as important in cancer. To date most studies have been focused on the PI3K/p110a isoform, which has been found to be mutated in several different cancers. The aim of our study was to determine which specific PI3K isoforms are involved in pancreatic ductal adenocarcinoma (PDAC) and investigate the effects of these isoforms on proliferation, survival, and induction of Akt activation in pancreatic cancer cells. Experimental Design: The expression of all PI3K isoforms and downstream targets was analyzed by immunohistochemistry in human pancreatic cancer tissue and normal counterparts. Isoform selective inhibitors and short interfering RNA (siRNA) were employed to investigate the effects of the different PI3Ks on proliferation, survival, and intracellular signaling in PDAC cell lines. Results: Immunohistochemical screening revealed high specific expression of the PI3K/p110? isoform. Scoring indicated that 72% of the PDAC tissue stained positive for PI3K/p110?, whereas no stain was detected in normal pancreatic ducts. Proliferation analyses after selective inhibition and siRNA downregulation of PI3K/p110? showed that PI3K/p110?, but not other PI3K isoforms, was required for cell proliferation. Overexpression of PI3K/p110? indeed increased cell numbers and mediated activation of Akt in PDAC cell lines. Moreover, PI3K/p110? was required for Akt activation via lysophosphatidic acid receptors. Conclusions: These data represent the first identification of a tumor-specific accumulation of the PI3K isoform p110? in human cancer. Further, our results signify a critical role for PI3K/p110? in pancreatic cancer, and we hypothesize that PI3K/p110? overexpression is a key event in the disease progression. ©2010 AACR.

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