Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members.
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.
DeFeo-Jones
Deborah
D
Department of Cancer Research, Merck Research Laboratories, Building 26-462, West Point, PA 19486, USA.
Barnett
Stanley F
SF
Fu
Sheng
S
Hancock
Paula J
PJ
Haskell
Kathleen M
KM
Leander
Karen R
KR
McAvoy
Elizabeth
E
Robinson
Ronald G
RG
Duggan
Mark E
ME
Lindsley
Craig W
CW
Zhao
Zhijian
Z
Huber
Hans E
HE
Jones
Raymond E
RE
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009369:Neoplasms / Q000201:enzymology*; D020033:Protein Isoforms / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D002867:Chromones; D009025:Morpholines; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020123:Sirolimus