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Int J Radiat Oncol Biol Phys. 2005 Mar 15;61(4):1183-8.

Inhibition of phosphatidylinositol-3-kinase causes cell death through a protein kinase B (PKB)-dependent mechanism and growth arrest through a PKB-independent mechanism.

Author information

  • 1Radiation Oncology, University of California, 1600 Divisadero St., San Francisco, CA 94143, USA. gottschalk@radonc17.ucsf.edu

Abstract

PURPOSE:

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 AND MATERIALS:

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.

CONCLUSION:

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.

PMID:
15752900
[PubMed - indexed for MEDLINE]
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