Targeting the phosphatidylinositol 3-kinase/Akt pathway for enhancing breast cancer cells to radiotherapy

Ke Liang, Weidong Jin, Christiane Knuefermann, Mathias Schmidt, Gordon B. Mills, K. Kian Ang, Luka Milas, Zhen Fan

    Research output: Contribution to journalArticle

    97 Scopus citations

    Abstract

    The phosphatidylinositol 3-kinase (PI-3K)/Akt pathway, regulated by its upstream growth factor receptor tyrosine kinases, plays a critical role in promoting cell proliferation and inhibiting cell death. The aim of this study was to determine whether the PI-3K/Akt activity contributes to the resistance of human breast cancer cells to ionizing radiation and whether inhibition of the PI-3K/Akt pathway could sensitize human breast cancer cells to radiotherapy. To determine a causal relationship between the activity of Akt and radioresistance in human breast cancer cells, MCF7 cells, transfected with constitutively active H-Ras (RadG12V) or constitutively active Akt, were chosen for analysis of the cell clonogenic survival fraction and induction of apoptosis after ionizing radiation. The PI-3K-specific inhibitor LY294002 was used to examine whether inhibition of PI-3K could sensitize these cells to radiation treatment. Our results indicate that the expression of constitutively active Ras (which activated Akt in a PI-3K-dependent manner) and the expression of constitutively active Akt (which caused a PI-3K-independent activation of Akt) each increased cellular resistance to radiation. Inhibition of PI-3K with LY294002 reverted the constitutively active Ras-mediated radioresistance but not the constitutively active Akt-mediated radioresistance. Our data suggest that Akt may be a potential target for enhancing the response to radiotherapy in patients with breast cancer.

    Original languageEnglish (US)
    Pages (from-to)353-360
    Number of pages8
    JournalMolecular cancer therapeutics
    Volume2
    Issue number4
    StatePublished - Apr 1 2003

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Liang, K., Jin, W., Knuefermann, C., Schmidt, M., Mills, G. B., Ang, K. K., Milas, L., & Fan, Z. (2003). Targeting the phosphatidylinositol 3-kinase/Akt pathway for enhancing breast cancer cells to radiotherapy. Molecular cancer therapeutics, 2(4), 353-360.