Proteasome inhibition by bortezomib increases IL-8 expression in androgen-independent prostate cancer cells: the role of IKKα.
Proteasome inhibition by bortezomib increases IL-8 expression in androgen-independent prostate cancer cells: the role of IKKα.
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DOI：
10.4049/jimmunol.1300895
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发表时间：
2013-09-01
期刊：
影响因子：
--
通讯作者：
Vancurova I
中科院分区：
文献类型：
--
作者：
Manna S;Singha B;Phyo SA;Gatla HR;Chang TP;Sanacora S;Ramaswami S;Vancurova I
受NFκB转录水平调控的促炎性和促血管生成趋化因子白介素-8 （IL-8）的表达在雄激素非依赖型转移性前列腺癌中组成性升高，并与不良预后相关。抑制nf κ b依赖性转录被用作抗癌策略，用于开发第一个临床批准的26S蛋白酶体抑制剂硼替佐米（BZ）。尽管BZ在血液系统恶性肿瘤中显示出显著的抗肿瘤活性，但在前列腺癌和其他实体肿瘤中效果较差；然而，其机制尚未被完全理解。本研究报告BZ对蛋白酶体的抑制意外地增加了雄激素非依赖性前列腺癌PC3和DU145细胞中IL-8的表达，而其他nf κ b调节基因的表达被抑制或不变。bz增加的IL-8表达与体外p65 NFκB DNA结合活性增加和p65募集到内源性IL-8启动子有关。此外，蛋白酶体抑制诱导了IKKα的核积累，IKKα酶活性的抑制显著减弱了bz诱导的p65对IL-8启动子的募集和IL-8的表达，表明诱导的IL-8表达至少部分是由IKKα介导的。总之，这些数据为前列腺癌细胞中蛋白酶体抑制IL-8表达的基因特异性增加提供了第一个证据，表明同时靶向IKKα和蛋白酶体可能提高BZ在雄激素非依赖型前列腺癌治疗中的有效性。
Expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8), which is regulated at the transcriptional level by NFκB, is constitutively increased in the androgen independent metastatic prostate cancer and correlates with poor prognosis. Inhibition of NFκB-dependent transcription was used as an anti-cancer strategy for the development of the first clinically approved 26S proteasome inhibitor, bortezomib (BZ). Even though BZ has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in prostate cancer and other solid tumors; however, the mechanisms have not been fully understood. Here we report that the proteasome inhibition by BZ unexpectedly increases the IL-8 expression in androgen independent prostate cancer PC3 and DU145 cells, while expression of other NFκB-regulated genes is inhibited or unchanged. The BZ-increased IL-8 expression is associated with increased in vitro p65 NFκB DNA binding activity and p65 recruitment to the endogenous IL-8 promoter. In addition, proteasome inhibition induces a nuclear accumulation of IKKα and inhibition of IKKα enzymatic activity significantly attenuates the BZ-induced p65 recruitment to IL-8 promoter and IL-8 expression, demonstrating that the induced IL-8 expression is mediated, at least partly, by IKKα. Together, these data provide the first evidence for the gene specific increase of IL-8 expression by the proteasome inhibition in prostate cancer cells and suggest that targeting both IKKα and the proteasome may increase the BZ effectiveness in androgen independent prostate cancer treatment.
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