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 androgenresponsive prostate cancer cells. The differential cytotoxic effects due to STI571 are associated with the nuclear level of Re1B in prostate cancer cells. STI571 inhibits IR-induced Re1B nuclear translocation, leading to increased radiosensitivity in aggressive androgen-independent PC-3 and DU-145 cells. In contrast, STI571 enhances Re1B nuclear translocation in androgen-responsive LNCaP cells. The different effects of STI571 on Re1B nuclear translocation are consistent with ReIB DNA binding activity and related target gene expression. STI571 inhibits the phosphoinositide 3-kinase-AKT-IκB kinase-α pathway in PC-3 cells by decreasing the phosphorylation levels of phosphoinositide 3-kinase (Tyr458) and AKT (Ser473), whereas STI571 increases NF-κB inducible kinase (Thr559) phosphorylation, leading to activation of IκB kinase-α in LNCaP cells. These results reveal that STI571 exhibits differential effects on the upstream kinases leading to different downstream effects on the NF-κB 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 Re1B.