Soft tissue sarcoma cells are highly sensitive to AKT blockade: A role for p53-independent up-regulation of GADD45α

Quan Sheng Zhu, Wenhong Ren, Borys Korchin, Guy Lahat, Adam Dicker, Yiling Lu, Gordon Mills, Raphael E. Pollock, Dina Lev

    Research output: Contribution to journalArticle

    40 Scopus citations

    Abstract

    The AKT signaling pathway is activated in soft tissue sarcoma (STS). However, AKT blockade has not yet been studied as a potential targeted therapeutic approach. Here, we examined the in vitro and in vivo effects of AKT inhibition in STS cells. Western blot analysis was used to evaluate the expression of AKT pathway components and the effect of AKT stimulation and inhibition on their phosphorylation. Cell culture assays were used to assess the effect of AKT blockade (using a phosphatidylinositol 3-kinase inhibitor and a specific AKT inhibitor) on STS cell growth, cell cycle, and apoptosis. Oligoarrays were used to determine gene expression changes in response to AKT inhibition. Reverse transcription-PCR was used for array validation. Specific small inhibitory RNA was used to knockdown GADD45α. Human STS xenografts in nude mice were used for in vivo studies, and immunohistochemistry was used to assess the effect of treatment on GADD45α expression, proliferation, and apoptosis. Multiple STS cell lines expressed activated AKT. AKT inhibition decreased STS downstream target phosphorylation and growth in vitro; G 2 cell cycle arrest and apoptosis were also observed. AKT inhibition induced GADD45α mRNA and protein expression in all STS cells treated independent of p53 mutational status. GADD45α knockdown attenuated the G2 arrest induced by AKT inhibition. In vivo, AKT inhibition led to decreased STS xenograft growth. AKT plays a critical role in survival and proliferation of STS cells. Modulation of AKT kinase activity may provide a novel molecularly based strategy for STS-targeted therapies.

    Original languageEnglish (US)
    Pages (from-to)2895-2903
    Number of pages9
    JournalCancer Research
    Volume68
    Issue number8
    DOIs
    StatePublished - Apr 15 2008

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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