title: Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation.
abstract: p90 ribosomal S6 kinase (RSK) is an important downstream effector of mitogen-activated protein kinase, but its biological functions are not well understood. We have now identified the first small-molecule, RSK-specific inhibitor, which we isolated from the tropical plant Forsteronia refracta. We have named this novel inhibitor SL0101. SL0101 shows remarkable specificity for RSK. The major determinant of SL0101-binding specificity is the unique ATP-interacting sequence in the amino-terminal kinase domain of RSK. SL0101 inhibits proliferation of the human breast cancer cell line MCF-7, producing a cell cycle block in G(1) phase with an efficacy paralleling its ability to inhibit RSK in intact cells. RNA interference of RSK expression confirmed that RSK regulates MCF-7 proliferation. Interestingly, SL0101 does not alter proliferation of a normal human breast cell line MCF-10A, although SL0101 inhibits RSK in these cells. We show that RSK is overexpressed in approximately 50% of human breast cancer tissue samples, suggesting that regulation of RSK has been compromised. Thus, we show that RSK has an unexpected role in proliferation of transformed cells and may be a useful new target for chemotherapeutic agents. SL0101 will provide a powerful new tool to dissect the molecular functions of RSK in cancer cells.
authors.affiliation: Center for Cell Signaling, Department of Pathology, University of Virginia Health Science Center, 7041 Multistory Building, Charlottesville, VA 22908-0577, USA. jas8j@virginia.edu
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Smith
authors.forename: Celeste E
authors.initials: CE
authors.lastname: Poteet-Smith
authors.forename: Yaming
authors.initials: Y
authors.lastname: Xu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Errington
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Hecht
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lannigan
mesh_terms: D000595:Amino Acid Sequence; D001578:Benzopyrans / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008969:Molecular Sequence Data; D009005:Monosaccharides / Q000494:pharmacology*; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
chemical_list: D001578:Benzopyrans; D009005:Monosaccharides; D010936:Plant Extracts; D047428:Protein Kinase Inhibitors; C497449:SL0101; D038744:Ribosomal Protein S6 Kinases, 90-kDa