title: Akti-1/2, an allosteric inhibitor of Akt 1 and 2, efficiently inhibits CaMKIα activity and aryl hydrocarbon receptor pathway.
abstract: 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.
authors.affiliation: Université de Rennes 1, Institut de Recherche Santé, Environnement et Travail, Rennes, France. david.gilot@univ-rennes1.fr
authors.forename: David
authors.initials: D
authors.lastname: Gilot
authors.forename: Fanny
authors.initials: F
authors.lastname: Giudicelli
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagadic-Gossmann
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1