RelB-dependent differential radiosensitization effect of STI571 on prostate cancer cells.
Radiation therapy is an effective treatment for localized prostate cancer. However, when high-risk factors are present, such as increased prostate-specific antigen, elevated Gleason scores and advanced T stage, undetected spreading of the cancer, and development of radiation-resistant cancer cells are concerns. Thus, additional therapeutic agents that can selectively sensitize advanced prostate cancer to radiation therapy are needed. Imatinib mesylate (Gleevec, STI571), a tyrosine kinase inhibitor, was evaluated for its potential to enhance the efficacy of ionizing radiation (IR) against aggressive prostate cancer cells. STI571 significantly enhances the IR-induced cytotoxicity of androgen-independent prostate cancer cells but not of androgen-responsive prostate cancer cells. The differential cytotoxic effects due to STI571 are associated with the nuclear level of RelB in prostate cancer cells. STI571 inhibits IR-induced RelB nuclear translocation, leading to increased radiosensitivity in aggressive androgen-independent PC-3 and DU-145 cells. In contrast, STI571 enhances RelB nuclear translocation in androgen-responsive LNCaP cells. The different effects of STI571 on RelB nuclear translocation are consistent with RelB DNA binding activity and related target gene expression. STI571 inhibits the phosphoinositide 3-kinase-AKT-IkappaB kinase-alpha pathway in PC-3 cells by decreasing the phosphorylation levels of phosphoinositide 3-kinase (Tyr458) and AKT (Ser473), whereas STI571 increases NF-kappaB inducible kinase (Thr559) phosphorylation, leading to activation of IkappaB kinase-alpha in LNCaP cells. These results reveal that STI571 exhibits differential effects on the upstream kinases leading to different downstream effects on the NF-kappaB alternative pathway in prostate cancer cells and suggest that STI571 is effective for the treatment of androgen-independent prostate cancer in the context of high constitutive levels of RelB. Mol Cancer Ther; 9(4); 803-12. (c)2010 AACR.
Xu
Yong
Y
Department of Radiation Medicine, University of Kentucky, College of Medicine, Lexington, KY 40536, USA.
Fang
Fang
F
Sun
Yulan
Y
St Clair
Daret K
DK
St Clair
William H
WH
D000728:Androgens / Q000494:pharmacology; D001549:Benzamides; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000528:radiation effects; D011839:Radiation, Ionizing; D015203:Reproducibility of Results; D051996:Transcription Factor RelA / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D000728:Androgens; D001549:Benzamides; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D000097782:NF-kappaB-Inducing Kinase; C497593:RELB protein, human