Bazedoxifene as a novel GP130 inhibitor for Colon Cancer therapy

Abstract

BackgroundInterleukin-11 (IL-11), a dominant IL-6 family cytokine, is involved in tumorigenesis, tumor progression and differentiation in colon cancer cells. IL-11 signaling has been recently identified as a potential therapeutic target in colon cancer. Bazedoxifene, a third- generation selective estrogen modulator approved by the Food and Drug Administration (FDA), is a novel inhibitor of IL-11/GP130 signaling discovered by docking modeling.MethodsIn this study, the inhibition efficacy of bazedoxifene in colon cancer cells and its potential mechanism were investigated in vitro and in vivo by using MTT cell viability assay, BrdU cell proliferation assay, colony formation assay, wound-healing/cell migration assay, immunofluorescence, western blot assay and the mouse xenograft tumor model.ResultsBazedoxifene inhibits phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and its nuclear translocation induced by IL-11 in colon cancer cells. It also inhibits p-STAT3 induced by IL-6 and IL-11 but not by OSM or STAT1 phosphorylation induced by INF-γ in human colon cancer cells. In addition, bazedoxifene can significantly inhibit phosphorylation of AKT and STAT3 downstream targets. Furthermore, bazedoxifene alone or together with oxaliplatin can significantly induce apoptosis, inhibit cell viability, cell colony formation and cell migration in colon cancer cells. Knock-down of IL-11R can reduce the sensitivity of colon cancer cells to bazedoxifene. IL-11 can reduce the efficacy of oxaliplatin-mediated inhibition of cell viability. Consistent with in vitro findings, bazedoxifene alone also attenuated HCT-15 xenograft tumor burden and reduced p-STAT3, p-AKT and p-ERK in vivo. Its combination with oxaliplatin attenuated DLD-1 xenograft tumor burden and reduced p-STAT3 in vivo.ConclusionsTaken together, these results support bazedoxifene as a novel and effective therapeutic agent targeting IL-11/GP130 signaling for human colorectal cancer therapy.