Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion

Authors

  • Sanjeev Shukla,

    1. Department of Urology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH
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  • Gregory T. MacLennan,

    1. Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH
    2. Case Comprehensive Cancer Center, Cleveland, OH
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  • Douglas J. Hartman,

    1. Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH
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  • Pingfu Fu,

    1. Case Comprehensive Cancer Center, Cleveland, OH
    2. Department of Epidemiology and Biostatistics, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH
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  • Martin I. Resnick,

    1. Department of Urology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH
    2. Case Comprehensive Cancer Center, Cleveland, OH
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  • Sanjay Gupta

    Corresponding author
    1. Department of Urology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH
    2. Case Comprehensive Cancer Center, Cleveland, OH
    • Department of Urology, The James and Eilleen Dicke Research Laboratory, Case Western Reserve University and University Hospitals Case Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106, USA
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Abstract

Activated phosphoinositide 3-kinase (PI3K) and its downstream target Akt/PKB are important signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis and oncogenesis. We investigated the role of the PI3K-Akt signaling pathway in the invasion of prostate cancer cell lines and activation of this pathway in primary human prostate tumors. Treatment of human prostate cancer cells viz. LNCaP, PC-3 and DU145 with PI3K pharmacological inhibitor, LY294002, potentially suppressed the invasive properties in each of these cell lines. Restoration of the PTEN gene to highly invasive prostate cancer PC-3 cells or expression of a dominant negative version of the PI3K target, Akt also significantly inhibited invasion and downregulated protein expression of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9, markers for cell invasion, indicating a central role of the PI3K-Akt pathway in this process. Immunoblot analysis of PI3K and total/activated levels of Akt showed increased protein levels of catalytic (p110α/β) and regulatory (p85) subunits of PI3K and constitutive Akt activation in high-grade tumors compared to low-grade tumor and benign tissue. Immunohistochemical analyses further confirmed a progressive increase in p-Akt (p-Ser473) levels but not of total-Akt (Akt1/2) in cancer tissues compared to benign specimens. A successive increase in p-Akt expression was further noted in specimens serially obtained from individuals with time-course disease progression. Taken together, these results suggest that aberrant activation of PI3K-Akt pathway may contribute to increased cell invasiveness and facilitate prostate cancer progression. © 2007 Wiley-Liss, Inc.

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