Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma

Georgios V. Georgakis, Yang Li, Georgios Z. Rassidakis, L. Jeffrey Medeiros, Gordon B. Mills, Anas Younes

    Research output: Contribution to journalArticle

    91 Scopus citations

    Abstract

    Activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been linked with tumour cell growth, survival and resistance to therapy in several cancer types. The active, phosphorylated form of Akt (pAkt) was found to be aberrantly expressed in Hodgkin lymphoma (HL)-derived cell lines and in Hodgkin-Reed-Sternberg (HRS) cells in 27 of 42 (64·3%) of primary lymph node sections of HL, indicative of PI3K activity. Akt phosphorylation was not associated with loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression, but with its phosphorylation in HL-cell lines, suggesting that its biological function is impaired. Akt phosphorylation was further induced by CD30 ligand (CD30L), CD40L and receptor activator of nuclear factor kappa B (RANK) ligand. The PI3K inhibitor LY294002 demonstrated antiproliferative effects in a dose- and time-dependent manner, which was associated with Akt dephosphorylation on Thr308 and Ser473 sites and dephosphorylation of the downstream ribosomal protein S6. LY209002 induced cell cycle arrest in the G0/G1 phase and apoptosis, which were associated with upregulation of MDM2, downregulation of cyclin D1, activation of caspase 9 and poly-ADP-ribose polymerase cleavage. The Akt inhibitor QLT394 also demonstrated antiproliferative effects in a dose- and time-dependent manner, dephosphorylated ribosomal S6 and cleaved caspase 9. Collectively, these data suggest that the aberrant activation of the PI3K/Akt survival pathway in HRS cells is not because of loss of PTEN expression. Our data suggest that PTEN phosphorylation and activation of CD30, CD40 and RANK may play a role in activating Akt in HRS cells.

    Original languageEnglish (US)
    Pages (from-to)503-511
    Number of pages9
    JournalBritish Journal of Haematology
    Volume132
    Issue number4
    DOIs
    StatePublished - Feb 1 2006

    Keywords

    • Akt
    • Apoptosis
    • CD30
    • CD40
    • Hodgkin lymphoma
    • Receptor activator of nuclear factor kappa B

    ASJC Scopus subject areas

    • Hematology

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