Chikusetsusaponin IVa Butyl Ester (CS-IVa-Be), a Novel IL6R Antagonist, Inhibits IL6/STAT3 Signaling Pathway and Induces Cancer Cell Apoptosis
| Autor: | Wuguang Lu, Chunping Hu, Shihui Qian, S. Paul Gao, Qiang Yu, Peng Cao, Yang Yang, Xiaoyan Sun, Xueting Cai, Jie Yang |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
STAT3 Transcription Factor
0301 basic medicine Cancer Research Programmed cell death Cell Survival Apoptosis Biology Stat3 Signaling Pathway TNF-Related Apoptosis-Inducing Ligand 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Neoplasms Humans Oleanolic Acid skin and connective tissue diseases Receptor Cell Proliferation Interleukin-6 Cell growth Drug Synergism Hep G2 Cells Saponins Receptors Interleukin-6 Molecular biology biological factors Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells Cancer research sense organs Signal transduction Signal Transduction |
| Zdroj: | Molecular Cancer Therapeutics. 15:1190-1200 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | The activation of IL6/STAT3 signaling is associated with the pathogenesis of many cancers. Agents that suppress IL6/STAT3 signaling have cancer-therapeutic potential. In this study, we found that chikusetsusaponin IVa butyl ester (CS-IVa-Be), a triterpenoid saponin extracted from Acanthopanas gracilistylus W.W.Smith, induced cancer cell apoptosis. CS-IVa-Be inhibited constitutive and IL6-induced STAT3 activation, repressed STAT3 DNA-binding activity, STAT3 nuclear translocation, IL6-induced STAT3 luciferase reporter activity, IL6-induced STAT3-regulated antiapoptosis gene expression in MDA-MB-231 cells, and IL6-induced TF-1 cell proliferation. Surprisingly, CS-IVa-Be inhibited IL6 family cytokines rather than other cytokines induced STAT3 activation. Further studies indicated that CS-IVa-Be is an antagonist of IL6 receptor via directly binding to the IL6Rα with a Kd of 663 ± 74 nmol/L and the GP130 (IL6Rβ) with a Kd of 1,660 ± 243 nmol/L, interfering with the binding of IL6 to IL6R (IL6Rα and GP130) in vitro and in cancer cells. The inhibitory effect of CS-IVa-Be on the IL6–IL6Rα–GP130 interaction was relatively specific as CS-IVa-Be showed higher affinity to IL6Rα than to LIFR (Kd: 4,910 ± 1,240 nmol/L) and LeptinR (Kd: 4,990 ± 915 nmol/L). We next demonstrated that CS-IVa-Be not only directly induced cancer cell apoptosis but also sensitized MDA-MB-231 cells to TRAIL-induced apoptosis via upregulating DR5. Our findings suggest that CS-IVa-Be as a novel IL6R antagonist inhibits IL6/STAT3 signaling pathway and sensitizes the MDA-MB-231 cells to TRAIL-induced cell death. Mol Cancer Ther; 15(6); 1190–200. ©2016 AACR. |
| Databáze: | OpenAIRE |
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