Inhibition of phosphatidylinositol-3-kinase causes increased sensitivity to radiation through a PKB-dependent mechanism

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

DOI:https://doi.org/10.1016/j.ijrobp.2005.08.014· OSTI ID:20706269

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

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1. Department of 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. Department of 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 increased radiosensitivity through inhibition of protein kinase B (PKB), implicating PKB as an important therapeutic target in prostate cancer. Methods and Materials: The prostate cancer cell line LNCaP was treated with the PI3K inhibitor LY294002, radiation, and combinations of the two therapies. Apoptosis and survival were measured by cell cycle analysis, Western blot analysis for cleaved poly (ADP-ribose) polymerase, and clonogenic survival. To test the hypothesis that inhibition of PKB is responsible for LY294002-induced radiosensitivity, LNCaP cells expressing a constitutively active form of PKB were used. Results: The combination of PI3K inhibition and radiation caused an increase in apoptosis and a decrease in clonogenic survival when compared to either modality alone. The expression of constitutively activated PKB blocked apoptosis induced by combination of PI3K inhibition and radiation and prevented radiosensitization by LY294002. Conclusion: These data indicate that PI3K inhibition increases sensitivity of prostate cancer cell lines to ionizing radiation through inactivation of PKB. Therefore, PTEN mutations, which lead to PKB activation, may play an important role in the resistance of prostate cancer to radiation therapy. Targeted therapy against PKB could be beneficial in the management of prostate cancer patients.

• OSTI ID: 20706269
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 4 Vol. 63; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ADP
APOPTOSIS
CARCINOMAS
CELL CYCLE
INHIBITION
IONIZING RADIATIONS
MUTATIONS
PROSTATE
PROTEINS
RADIOSENSITIVITY
RADIOTHERAPY
RIBOSE
SENSITIVITY