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首页> 外文期刊>Molecular cancer therapeutics >RelB-dependent differential radiosensitization effect of STI571 on prostate cancer cells.
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RelB-dependent differential radiosensitization effect of STI571 on prostate cancer cells.

机译：STI571对RelB的差异放射增敏作用对前列腺癌细胞的影响。

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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.
机译：放射疗法是局部前列腺癌的有效治疗方法。但是，当存在高风险因素时，例如前列腺特异性抗原增加，格里森评分升高和晚期T期，未检测到的癌症扩散以及抗辐射癌细胞的发展，这些都是令人关注的问题。因此，需要能够选择性地使晚期前列腺癌对放射疗法敏感的其他治疗剂。甲磺酸伊马替尼（Gleevec，STI571），一种酪氨酸激酶抑制剂，被评估了其增强电离辐射（IR）对侵袭性前列腺癌细胞功效的潜力。 STI571显着增强了IR诱导的雄激素非依赖性前列腺癌细胞的细胞毒性，但没有增强雄激素反应性前列腺癌细胞的细胞毒性。 STI571引起的不同细胞毒性作用与前列腺癌细胞中RelB的核水平有关。 STI571抑制IR诱导的RelB核易位，导致侵袭性雄激素非依赖性PC-3和DU-145细胞的放射敏感性增加。相反，STI571增强了雄激素反应性LNCaP细胞中的RelB核易位。 STI571对RelB核易位的不同影响与RelB DNA结合活性和相关靶基因表达一致。 STI571通过降低磷酸肌醇3-激酶（Tyr458）和AKT（Ser473）的磷酸化水平来抑制PC-3细胞中的磷酸肌醇3-激酶-AKT-IkappaB激酶-α途径，而STI571增加NF-kappaB诱导型激酶（Thr559）磷酸化，导致LNCaP细胞中IkappaB激酶-α活化。这些结果表明，STI571对上游激酶表现出不同的作用，从而导致对前列腺癌细胞中NF-kappaB替代途径的不同下游作用，并且表明STI571在高组成水平的情况下可有效治疗非雄激素依赖性前列腺癌。 RelB。分子癌疗法; 9（4）; 803-12。 （c）2010年美国机管学会（AACR）。

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