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      Inhibition of Akt signaling in hepatoma cells induces apoptotic cell death independent of Akt activation status

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      Author
      Buontempo, F.
      Ersahin, T.
      Missiroli, S.
      Senturk, S.
      Etro, D.
      Ozturk, M.
      Capitani, S.
      Cetin Atalay, R.
      Neri, M. L.
      Date
      2011
      Source Title
      Investigational New Drugs
      Print ISSN
      0167-6997
      Publisher
      Springer
      Volume
      29
      Issue
      6
      Pages
      1303 - 1313
      Language
      English
      Type
      Article
      Item Usage Stats
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      Abstract
      The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is involved in cell survival and anti-apoptotic signaling. Akt has been shown to be constitutively expressed in a variety of human tumors including hepatocellular carcinoma (HCC). In this report we analyzed the status of Akt pathway in three HCC cell lines, and tested cytotoxic effects of Akt pathway inhibitors LY294002, Wortmannin and Inhibitor VIII. In Mahlavu human hepatoma cells Akt was constitutively activated, as demonstrated by its Ser473 phosphorylation, downstream hyperphosphorylation of BAD on Ser136, and by a specific cell-free kinase assay. In contrast, Huh7 and HepG2 did not show hyperactivation when tested by the same criteria. Akt enzyme hyperactivation in Mahlavu was associated with a loss of PTEN protein expression. Akt signaling was inhibited by the upstream kinase inhibitors, LY294002, Wortmannin, as well as by the specific Akt Inhibitor VIII in all three hepatoma cell lines. Cytotoxicity assays with Akt inhibitors in the same cell lines indicated that they were all sensitive, but with different IC50 values as assayed by RT-CES. We also demonstrated that the cytotoxic effect was through apoptotic cell death. Our findings provide evidence for its constitutive activation in one HCC cell line, and that HCC cell lines, independent of their Akt activation status respond to Akt inhibitors by apoptotic cell death. Thus, Akt inhibition may be considered as an attractive therapeutic intervention in liver cancer. © Springer Science+Business Media, LLC 2010.
      Keywords
      Akt
      HCC
      Inhibitor VIII
      LY294002
      PI3K
      PTEN
      RTCES
      Wortmannin
      Permalink
      http://hdl.handle.net/11693/21701
      Published Version (Please cite this version)
      http://dx.doi.org/10.1007/s10637-010-9486-3
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