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.
Keywords: NFkappaB, kinase, inflammation, RSK2, ERK, Vasculature, cancer, histone H3, Sophora flavescens, Interleukin-6, post-menopausal, osteoporosis, endometrium, prostate
Endocrine, Metabolic & Immune Disorders - Drug Targets
Title: Attenuation of ERK/RSK2-Driven NFκB Gene Expression and Cancer Cell Proliferation by Kurarinone, a Lavandulyl Flavanone Isolated from Sophora flavescens Ait. Roots
Volume: 11 Issue: 3
Author(s): Wim Vanden Berghe, An De Naeyer, Nathalie Dijsselbloem, Jean-Pierre David, Denis De Keukeleire and Guy Haegeman
Affiliation:
Keywords: NFkappaB, kinase, inflammation, RSK2, ERK, Vasculature, cancer, histone H3, Sophora flavescens, Interleukin-6, post-menopausal, osteoporosis, endometrium, prostate
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.
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Vanden Berghe Wim, De Naeyer An, Dijsselbloem Nathalie, David Jean-Pierre, De Keukeleire Denis and Haegeman Guy, Attenuation of ERK/RSK2-Driven NFκB Gene Expression and Cancer Cell Proliferation by Kurarinone, a Lavandulyl Flavanone Isolated from Sophora flavescens Ait. Roots, Endocrine, Metabolic & Immune Disorders - Drug Targets 2011; 11 (3) . https://dx.doi.org/10.2174/187153011796429790
DOI https://dx.doi.org/10.2174/187153011796429790 |
Print ISSN 1871-5303 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3873 |
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