Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Universitätsstrasse 1, Düsseldorf 40225, Germany.
Cell Death Dis. 2013 Oct 17;4(10):e859. doi: 10.1038/cddis.2013.386.
The p90 ribosomal S6 kinase (RSK) family is a group of highly conserved Ser/Thr kinases that promote cell proliferation, growth, motility and survival. As they are almost exclusively activated downstream of extracellular signal-regulated kinases 1 and 2 (ERK1/2), therapeutic intervention by RSK inhibition is less likely to produce such severe side effects as those observed following inhibition of the upstream master regulators Raf, MEK and ERK1/2. Here, we report that BI-D1870, a potent small molecule inhibitor of RSKs, induces apoptosis, although preferentially, in a p21-deficient background. On the other hand, BI-D1870 also induces a strong transcription- and p53-independent accumulation of p21 protein and protects cells from gamma irradiation (γIR)-induced apoptosis, driving them into senescence even in the absence of γIR. Although we identified p21 in in vitro kinase assays as a novel RSK substrate that specifically becomes phosphorylated by RSK1-3 at Ser116 and Ser146, RNA-interference, overexpression and co-immunoprecipitation studies as well as the use of SL0101, another specific RSK inhibitor, revealed that BI-D1870 mediates p21 accumulation via a yet unknown pathway that, besides its off-site targets polo-like kinase-1 and AuroraB, also does also not involve RSKs. Thus, this novel off-target effect of BI-D1870 should be taken into serious consideration in future studies investigating the role of RSKs in cellular signaling and tumorigenesis.
p90 核糖体 S6 激酶（RSK）家族是一组高度保守的 Ser/Thr 激酶，可促进细胞增殖、生长、运动和存活。由于它们几乎完全在细胞外信号调节激酶 1 和 2（ERK1/2）下游被激活，因此 RSK 抑制的治疗干预不太可能产生如抑制上游主调控因子 Raf、MEK 和 ERK1/2 所观察到的那样严重的副作用。在这里，我们报告说，BI-D1870 是一种有效的 RSK 小分子抑制剂，尽管在 p21 缺陷背景下优先诱导细胞凋亡。另一方面，BI-D1870 还诱导强烈的转录和 p53 非依赖性 p21 蛋白积累，并保护细胞免受γ辐射（γIR）诱导的凋亡，即使在没有 γIR 的情况下，也将它们驱动进入衰老状态。虽然我们在体外激酶测定中确定 p21 是一种新型的 RSK 底物，可特异性地在 Ser116 和 Ser146 处被 RSK1-3 磷酸化，但 RNA 干扰、过表达和共免疫沉淀研究以及 SL0101（另一种特异性 RSK 抑制剂）的使用表明，BI-D1870 通过一种尚未确定的途径介导 p21 积累，该途径除了其非靶标 polo 样激酶-1 和 AuroraB 外，还不涉及 RSK。因此，在未来研究 RSK 在细胞信号转导和肿瘤发生中的作用时，应该认真考虑 BI-D1870 的这种新的非靶标效应。
