Akti-1/2, an allosteric inhibitor of Akt 1 and 2, efficiently inhibits CaMKIα activity and aryl hydrocarbon receptor pathway. - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Chemico-Biological Interactions Année : 2010

Akti-1/2, an allosteric inhibitor of Akt 1 and 2, efficiently inhibits CaMKIα activity and aryl hydrocarbon receptor pathway.

Résumé

Deregulation of the phosphatidylinositol 3 (PI3) kinase/Akt pathway, resulting in enhanced Akt activity, is one of the most frequent changes in human cancer. Akt has therefore attracted significant attention as an anticancer target in recent years and many Akt inhibitors have been identified, especially Akti-1/2, a non-ATP competitive inhibitor of Akt isoforms 1 and 2. In this study, our results suggest that caution may be required when using Akti-1/2 as a specific inhibitor of Akt since it perfectly inhibits Ca(2+)/CaM-dependent protein kinase (CaMK) Iα activity. Akti-1/2 was thus able to inhibit recombinant CaMKIα activity as efficiently as the CaMK inhibitor KN-93. Moreover, Akti-1/2 prevented the nuclear translocation of aryl hydrocarbon receptor (AhR) in MCF-7 cells in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, which has been demonstrated to require CaMKI activity. In addition, our results, obtained with a large panel of structurally-unrelated PI3K inhibitors, make unlikely any contribution of PI3K/Akt activity to the AhR pathway. To the best of our knowledge, this is the first report showing that Akti-1/2 has off-target effects at concentration equipotent with Akt inhibition. This may impact on the therapeutic application of Akti-1/2 and structurally-related compounds.

Dates et versions

hal-00696150 , version 1 (11-05-2012)

Identifiants

Citer

David Gilot, Fanny Giudicelli, Dominique Lagadic-Gossmann, Olivier Fardel. Akti-1/2, an allosteric inhibitor of Akt 1 and 2, efficiently inhibits CaMKIα activity and aryl hydrocarbon receptor pathway.. Chemico-Biological Interactions, 2010, 188 (3), pp.546-52. ⟨10.1016/j.cbi.2010.08.011⟩. ⟨hal-00696150⟩
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