Data from Chikusetsusaponin IVa Butyl Ester (CS-IVa-Be), a Novel IL6R Antagonist, Inhibits IL6/STAT3 Signaling Pathway and Induces Cancer Cell Apoptosis

Abstract

<div>Abstract<p>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 <i>Acanthopanas gracilistylus</i> 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 <i>K</i><sub>d</sub> of 663 ± 74 nmol/L and the GP130 (IL6Rβ) with a <i>K</i><sub>d</sub> of 1,660 ± 243 nmol/L, interfering with the binding of IL6 to IL6R (IL6Rα and GP130) <i>in vitro</i> 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 (<i>K</i><sub>d</sub>: 4,910 ± 1,240 nmol/L) and LeptinR (<i>K</i><sub>d</sub>: 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. <i>Mol Cancer Ther; 15(6); 1190–200. ©2016 AACR</i>.</p></div>