title: The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1.
abstract: 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.
authors.affiliation: Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Universitätsstrasse 1, Düsseldorf 40225, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Neise
authors.forename: D
authors.initials: D
authors.lastname: Sohn
authors.forename: A
authors.initials: A
authors.lastname: Stefanski
authors.forename: H
authors.initials: H
authors.lastname: Goto
authors.forename: M
authors.initials: M
authors.lastname: Inagaki
authors.forename: S
authors.initials: S
authors.lastname: Wesselborg
authors.forename: W
authors.initials: W
authors.lastname: Budach
authors.forename: K
authors.initials: K
authors.lastname: Stühler
authors.forename: R U
authors.initials: RU
authors.lastname: Jänicke
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D064127:Aurora Kinases / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects* / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism* / Q000494:pharmacology; D005720:Gamma Rays; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009005:Monosaccharides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000528:radiation effects; D013379:Substrate Specificity / Q000187:drug effects / Q000528:radiation effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D064127:Aurora Kinases; D001578:Benzopyrans; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007527:Isoenzymes; D009005:Monosaccharides; D010768:Phosphoserine; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C516541:BI D1870; C497449:SL0101