Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members.

Abstract

Recent studies indicate that dysregulation of the Akt/PKB family of serine/threonine kinases is a prominent feature of many human cancers. The Akt/PKB family is composed of three members termed Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma. It is currently not known to what extent there is functional overlap between these family members. We have recently identified small molecule inhibitors of Akt. These compounds have pleckstrin homology domain-dependent, isozyme-specific activity. In this report, we present data showing the relative contribution that inhibition of the different isozymes has on the apoptotic response of tumor cells to a variety of chemotherapies. In multiple cell backgrounds, maximal induction of caspase-3 activity is achieved when both Akt1 and Akt2 are inhibited. This induction is not reversed by overexpression of functionally active Akt3. The level of caspase-3 activation achieved under these conditions is equivalent to that observed with the phosphatidylinositol-3-kinase inhibitor LY294002. We also show that in different tumor cell backgrounds inhibition of mammalian target of rapamycin, a downstream substrate of Akt, is less effective in inducing caspase-3 activity than inhibition of Akt1 and Akt2. This shows that the survival phenotype conferred by Akt can be mediated by signaling pathways independent of mammalian target of rapamycin in some tumor cell backgrounds. Finally, we show that inhibition of both Akt1 and Akt2 selectively sensitizes tumor cells, but not normal cells, to apoptotic stimuli.

11 Figures and Tables

050100150'05'06'07'08'09'10'11'12'13'14'15'16'17
Citations per Year

660 Citations

Semantic Scholar estimates that this publication has 660 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{DefeoJones2005TumorCS, title={Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members.}, author={Deborah Defeo-Jones and Stanley F Barnett and Sheng Yang Fu and Paula J Hancock and Kathleen M. Haskell and Karen R. Leander and Elizabeth M. McAvoy and Ronald G Robinson and Mark E. Duggan and Craig W Lindsley and Zhijian Zhao and Hans E. Huber and Raymond E. Jones}, journal={Molecular cancer therapeutics}, year={2005}, volume={4 2}, pages={271-9} }