Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation.
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.
Smith
Jeffrey A
JA
Center for Cell Signaling, Department of Pathology, University of Virginia Health Science Center, 7041 Multistory Building, Charlottesville, VA 22908-0577, USA. jas8j@virginia.edu
Poteet-Smith
Celeste E
CE
Xu
Yaming
Y
Errington
Timothy M
TM
Hecht
Sidney M
SM
Lannigan
Deborah A
DA
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
D001578:Benzopyrans; D009005:Monosaccharides; D010936:Plant Extracts; D047428:Protein Kinase Inhibitors; C497449:SL0101; D038744:Ribosomal Protein S6 Kinases, 90-kDa