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: Wim Vanden Berghe, An De Naeyer, Nathalie Dijsselbloem, Jean-Pierre David, Denis De Keukeleire, Guy Haegeman
• Journal: Endocrine, metabolic & immune disorders drug targets (Endocr Metab Immune Disord Drug Targets) Vol. 11 Issue 3 Pg. 247-61 (Sep 01 2011) ISSN: 2212-3873 [Electronic] United Arab Emirates
• PMID: 21831037 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Flavanones
• Flavonoids
• Plant Extracts
• kurarinone
• Protein Serine-Threonine Kinases
• Ribosomal Protein S6 Kinases, 90-kDa
• ribosomal protein S6 kinase, 90kDa, polypeptide 3
• Extracellular Signal-Regulated MAP Kinases
• NF-kappa B kinase

Topics

• Animals
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, physiology)
• Female
• Flavanones (isolation & purification, pharmacology)
• Flavonoids (isolation & purification, pharmacology)
• Gene Expression Regulation, Enzymologic
• Humans
• MAP Kinase Signaling System (genetics)
• Mice
• Plant Extracts (isolation & purification, pharmacology)
• Plant Roots
• Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Ribosomal Protein S6 Kinases, 90-kDa (antagonists & inhibitors, physiology)
• Sophora (enzymology, metabolism)