Inhibition of phosphatidylinositol-3-kinase causes cell death through a protein kinase B (PKB)-dependent mechanism and growth arrest through a PKB-independent mechanism.
OBJECTIVE
To identify whether inhibition of phosphatidylinositol-3-kinase (PI3K) causes apoptosis through inhibition of protein kinase B (PKB), implicating PKB as an important therapeutic target in prostate cancer.


METHODS
After treatment with the PI3K inhibitor, LY294002, proliferation and apoptosis of the prostate cancer cell line, LNCaP, were measured by cell cycle analysis and cleavage of poly (ADP-ribose) polymerase. To test the hypothesis that inhibition of PKB is responsible for the LY294002-induced apoptosis, LNCaP cells expressing a constitutively active form of PKB were generated.


RESULTS
Treatment of LNCaP cells with the PI3K inhibitor, LY294002, caused inactivation of PKB, growth arrest, and apoptosis. LY294002-induced apoptosis was increased in the absence of serum. The G1 growth arrest was associated with an increase in p27(kip1) expression. Cells expressing constitutively active PKB were protected from apoptosis induced by LY294002, but not from the G1 growth arrest induced by PI3K inhibition.


CONCLUSIONS
These data suggest that PKB activity regulates apoptosis, but not G1 arrest, and identify PKB as a potential critical target for cancer therapy. Targeted therapy against kinases might complement more conventional therapies, including androgen suppression for prostate cancer.
Gottschalk
Alexander R
AR
Radiation Oncology, University of California, 1600 Divisadero St., San Francisco, CA 94143, USA. gottschalk@radonc17.ucsf.edu
Doan
Albert
A
Nakamura
Jean L
JL
Haas-Kogan
Daphne A
DA
Stokoe
David
D
D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt