title: Attenuation of ERK/RSK2-driven NFκB gene expression and cancer cell proliferation by kurarinone, a lavandulyl flavanone isolated from Sophora flavescens ait. roots.
abstract: We have analyzed in molecular detail how kurarinone, a lavandulyl flavanone isolated from Sophora flavescens, suppresses nuclear factor-κB (NFκB)-driven interleukin-6 (IL6) expression and cancer cell growth. Interleukin-6 (IL6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes responsivity to hormones and to chemotherapeutics. Our results in estrogen-unresponsive fibroblasts, ribosomal S6 kinase 2 kinase (RSK2) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that kurarinone can inhibit tumor cell proliferation and selectively block nuclear NFκB transactivation of specific target genes such as IL6, cyclin D1, SOD2 but not TNFAIP2. This occurs via attenuation of extracellular signal-regulated protein (ERK) and RSK2 kinase pathways and inhibition of S6 kinase ribosomal protein (S6RP) and histone H3 S10 phosphorylation. As constitutive NFκB and RSK2 activity are important hallmarks of human cancers, including hematopoietic malignancies and solid tumors, prenylated flavanones represent an attractive class of natural inhibitors of the ERK/RSK2 signaling pathway for cancer therapy.
authors.affiliation: Ghent University (UGent), Department of Physiology, Laboratory of Eukaryotic Gene Expression and Signal Transduction, Ledeganckstraat, Ghent, Belgium. wim.vandenberghe@ua.ac.be
authors.forename: Wim Vanden
authors.initials: WV
authors.lastname: Berghe
authors.forename: An
authors.initials: A
authors.lastname: De Naeyer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dijsselbloem
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
authors.forename: Denis
authors.initials: D
authors.lastname: De Keukeleire
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D005260:Female; D044950:Flavanones / Q000302:isolation & purification / Q000494:pharmacology; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology; D018517:Plant Roots; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000502:physiology*; D029909:Sophora / Q000201:enzymology / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D044950:Flavanones; D005419:Flavonoids; D010936:Plant Extracts; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D000097782:NF-kappaB-Inducing Kinase; C411319:kurarinone; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3