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

Journal Article · Tue Mar 15 04:00:00 EST 2005 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2004.12.024· OSTI ID:20696149

Gottschalk, Alexander R ^[1]; Doan, Albert ^[2]; Nakamura, Jean L ^[2]; Haas-Kogan, Daphne A ^[2]; Stokoe, David Ph.D. ^[3]

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1. Radiation Oncology, University of California, San Francisco, San Francisco, CA (United States) and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA (United States)
2. Radiation Oncology, University of California, San Francisco, San Francisco, CA (United States)
3. Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA (United States)

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{sup 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.

• OSTI ID: 20696149
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 4 Vol. 61; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ADP
ANDROGENS
APOPTOSIS
CARCINOMAS
CELL CYCLE
CLEAVAGE
INHIBITION
PHOSPHOTRANSFERASES
PROSTATE
RIBOSE