Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling

Abstract

BackgroundInterleukin-6 (IL-6) is a multifunctional cytokine, which is involved in the regulation of differentiation and growth of certain types of tumor cells. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) induced by IL-6 is frequently detected in liver cancer and has emerged as a viable molecular target for liver cancer treatment. However, few inhibitors targeting up-streams of STAT3 are available for the therapy of liver cancer. We reported the discovery of EVISTA (Raloxifene HCl) as novel inhibitor of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Raloxifene in STAT3 signaling or liver cancer cells is still unclear.ResultsRaloxifene inhibited the P-STAT3 stimulated by IL-6, but not the induction of STAT1 and STAT6 phosphorylation by IFN-γ, IFN-α, and IL-4. Raloxifene inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell-lines. Raloxifene inhibited the targets of STAT3, such as Bcl-2, Bcl-xl and survivin and cell viability, cell migration, and colony formation in liver cancer cells. Further, daily administration of Raloxifene suppressed the Hep-G2 tumor growth in mice in vivo.Materials and MethodsThe inhibitory effect on STAT3 phosphorylation and activity as well as cell viability, migration, and colony forming ability by Raloxifene was examined in human liver cancer cells. Tumor growth was detected via mouse xenograft tumor mode.ConclusionsOur results suggest that Raloxifene is a potent IL-6/GP130 inhibitor and may be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling.

Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene

“…Our cooperative group previously found that the N and O of the piperidinyl-ethoxy moiety of raloxifene could form hydrogen bonds with Asn92 and Cys6 residue of gp130 D1 domain, which disrupts the native IL-6 binding interaction with the gp130 [ 15 ]. Raloxifene was proved to downregulate the IL-6-induced STAT3 phosphorylation in pancreatic and hepatic cancer cells [ 15 , 16 ], which indicates that raloxifene is an effective IL-6/gp130 inhibitor. In vitro study, raloxifene was proved to downregulate the STAT3 phosphorylation induced by IL-6 in hepatic cancer cells, but not the induction of STAT1 and STAT6 phosphorylation by IFN- γ , IFN- α , and IL-4 [ 16 ].…”

“…Raloxifene is approved by the FDA for the prevention and treatment of postmenopausal osteoporosis [ 14 ]. It has been discovered as a novel inhibitor of the IL-6/gp130 interface recently and inhibits the phosphorylation of STAT3 in cancer cells in our previous studies [ 15 , 16 ]. The protective effect of raloxifene in cardiac remodeling and dysfunction induced by pressure overload is contradictory as previous studies reported [ 17 , 18 ]; moreover, the potential molecular mechanism and anti-inflammation effect of raloxifene in the cardiovascular system are unclear likewise.…”

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

“…This suggests that expression levels of gp130 may be relevant as a biomarker in patient selection for targeted anti‐IL6 or anti‐IL11 treatments. An anti‐tumorigenic effects of bazedoxifene , associated with reduced IL6‐dependent pSTAT3 levels, have been demonstrated in xenograft models of rhabdomyosarcoma (Xiao et al , ), pancreatic (Wu et al , ), liver (Wang et al , ), and colon cancer (Li et al , ). Our data comprehensively extend these observations and demonstrate significant anti‐tumorigenic effects of bazedoxifene in multiple IL11‐dependent and immune‐competent models of spontaneous gastric, intestinal, and colon cancer.…”

IL-6 family cytokines: Key inflammatory mediators as biomarkers and potential therapeutic targets

“…Another example of IL-6 suppression is the mechanism of Quercetin, a compound found in many plant-based foods, which has been proposed for chemoprevention and treatment of glioblastoma [78]. Finally, the estrogen receptor modulator Evista (Raloxifene HCl), found to also inhibit IL-6/GP130 protein interaction, represents a promising chemopreventive agent for breast, colon, multiple myeloma and liver cancer [79] [80].…”