Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1)

摘要: // Kristen M. Reipas 1 , Jennifer H. Law Nicole Couto Sumaiya Islam Yvonne Li 2 Huifang 3 Artem Cherkasov Karen Jung 4 Amarpal S. Cheema Steven J. Jones John A. Hassell 5 Sandra E. Dunn Laboratory for Oncogenomic Research, Child and Family Research Institute, University of British Columbia, Vancouver, Canada, Genome Science Centre, BC Cancer Agency, Canada. Vancouver Prostate Experimental Oncology, Alberta, Edmonton, Alberta. Center Functional Genomics, McMaster University, Ontario, Correspondence: Dunn, email: Keywords : Triple-negative breast cancer, p90 ribosomal S6 kinase, Y-box binding protein-1, tumor-initiating cells, drug repositioning Received January 26, 2013 Accepted February Published 27, Abstract cancers (TNBC) are notoriously difficult to treat because they lack hormone receptors have limited targeted therapies. Recently, we demonstrated that kinase (RSK) is essential TNBC growth survival indicating it as a target therapeutic development. RSK phosphorylates protein-1 (YB-1), an oncogenic transcription/translation factor, highly expressed in (~70% cases) associated with poor prognosis, resistance tumor initiation. YB-1 regulates the cell markers, CD44 CD49f however its role Notch signaling has not been explored. We sought identify novel chemical entities inhibitory activity. The Prestwick Chemical Library 1120 off-patent drugs was screened inhibitors using both vitro assays molecular docking. lead candidate, luteolin, inhibited RSK1 RSK2 activity suppressed TNBC, including TIC-enriched populations. Combining luteolin paclitaxel increased death unlike chemotherapy alone, did enrich + cells. Luteolin’s efficacy against drug-resistant cells further indicated primary x43 line, where monolayer mammosphere formation. next endeavored understand how inhibition RSK/YB-1 by elicited effect on ChIP-on-ChIP experiments SUM149 revealed 12-fold enrichment Notch4 promoter. chose pursue this there several reports maintains undifferentiated, TIC state. Herein report silencing siRNA decreased mRNA. Conversely, transient expression Flag:YB-1 WT or constitutively active mutant D102 levels transcript abundance intracellular domain (N4ICD) correlated activation P-RSK S221/7 P-YB-1 S102 panel lines. Silencing reduced mRNA corresponded loss N4ICD. Likewise, inhibitors, BI-D1870, thereby Notch4. In conclusion, inhibiting pathway approach blocking such provides means TICs.