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.