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Pathobiological implications of the expression of EGFR, pAkt, NF-κB and MIC-1 in prostate cancer stem cells and their progenies.

Abstract

The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse. The present study was undertaken to establish the possibility of using a combination of specific oncogenic products, including epidermal growth factor receptor (EGFR), pAkt, nuclear factor-kappaB (NF-κB) and macrophage inhibitory cytokine-1 (MIC-1) as biomarkers and therapeutic targets for optimizing the management of patients with localized PC at earlier disease stages. The immunohistochemical and immunofluorescence data have revealed that the expression levels of EGFR, Ser(473)-pAkt, NF-κB p65 and MIC-1 proteins were significantly enhanced in the same subset of 76 cases of prostatic adenocarcinoma specimens during the disease progression and these biomarkers were expressed in a small subpopulation of CD133(+) PC cells and the bulk tumor mass of CD133(-) PC cells. Importantly, all of these biomarkers were also overexpressed in 80-100% of 30 PC metastasis bone tissue specimens. Moreover, the results have indicated that the EGF-EGFR signaling pathway can provide critical functions for the self-renewal of side population (SP) cells endowed with stem cell-like features from highly invasive WPE1-NB26 cells. Of therapeutic interest, the targeting of EGFR, pAkt, NF-κB or MIC-1 was also effective at suppressing the basal and EGF-promoted prostasphere formation by SP WPE1-NB26 cells, inducing disintegration of SP cell-derived prostaspheres and decreasing the viability of SP and non-SP WPE1-NB26 cell fractions. Also, the targeting of these oncogenic products induced the caspase-dependent apoptosis in chemoresistant SP WPE1-NB26 cells and enhanced their sensibility to the cytotoxic effects induced by docetaxel. These findings suggest that the combined use of EGFR, pAkt, NF-κB and/or MIC-1 may represent promising strategies for improving the accuracy of current diagnostic and prognostic methods and efficacy of treatments of PC patients in considering the disease heterogeneity, thereby preventing PC progression to metastatic and lethal disease states.

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  • Authors

    Mimeault M, Johansson SL, Batra SK

    Source

    PloS one 7:2 2012 pg e31919

    MeSH

    Antigens, CD
    Cell Proliferation
    Disease Progression
    Epidermal Growth Factor
    Gene Expression Regulation, Neoplastic
    Glycoproteins
    Growth Differentiation Factor 15
    Humans
    Immunohistochemistry
    In Situ Nick-End Labeling
    Male
    Microscopy, Confocal
    Microscopy, Fluorescence
    NF-kappa B
    Neoplastic Stem Cells
    Peptides
    Prostatic Neoplasms
    Proto-Oncogene Proteins c-akt
    Receptor, Epidermal Growth Factor

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22384099