Jilai Tian1,2,3, Xiang Chen3, Shengling Fu3, Ruijie Zhang3, Li Pan3, Yang Cao4, Xiaojuan Wu5, Hui Xiao6, Huey-Jen Lin7, Hui-Wen Lo8, Ying Zhang9, Jiayuh Lin10. 1. Key Laboratory of Drug Target and Drug for Degenerative Disease, Jiangsu Province, Department of Pharmacology, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China. 2. Collaborative Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou, 215123, Jiangsu, China. 3. Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD, 21201, USA. 4. Department of Hematology & Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. 5. Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. 6. The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43205, USA. 7. Department of Medical Laboratory Sciences, University of Delaware, Newark, DE, 19716, USA. 8. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA. 9. Department of Rheumatoid and Immunity, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China. 10. Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD, 21201, USA. JLin@som.umaryland.edu.
Abstract
PURPOSE: Triple-negative breast cancer (TNBC) has been ranked as one of the devastating malignancy worldwide. Its disease progression and treatment obstacle is associated with the negligible expression of estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-). Due to a lack of growth hormone receptors, TNBC is desperately demanding effective therapeutic regimens. A growing body of evidence indicated that glycoprotein 130 kDa (GP130), the pivotal mediator involved in interleukin 6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, is strongly correlated with tumor progression. Therefore, GP130 could become a novel target for treating TNBC. In our earlier studies, we demonstrated bazedoxifene as being a novel GP130 inhibitor. METHODS: In the current report, anti-tumor effect of bazedoxifene on TNBC was further evaluated in TNBC cell lines SUM159, MDA-MB-231, and MDA-MB-468. We assessed anti-TNBC potency of bazedoxifene by carrying out various analysis encompassing western blot, cell proliferation, cell migration, colony formation, and growth of tumors in the xenograft mice. RESULTS: Our findings demonstrated that bazedoxifene not only decreased the expression of P-STAT3, IL-6/GP130-mediated downstream target genes P-AKT and P-ERK, but also blocked mitogen effects stimulated by IL-6, including cell viability, and overall cell survive, proliferation as well as cell migration. Likewise in laboratory animal model, tumor growth in mice was remarkably suppressed by bazedoxifene via an oral administration route. Combinational treatment of bazedoxifene plus the conventional chemotherapeutic agent, paclitaxel, synergistically impeded cell viability, colony formation, and cell migration far more significantly than the one from single-drug alone. CONCLUSIONS: Taken together, our data suggest that bazedoxifene may be developed as a promising small molecular therapeutic agent for eradicating TNBC intrinsically associated with constitutively active IL-6/GP130/STAT3 signaling cascade.
PURPOSE: Triple-negative breast cancer (TNBC) has been ranked as one of the devastating malignancy worldwide. Its disease progression and treatment obstacle is associated with the negligible expression of estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-). Due to a lack of growth hormone receptors, TNBC is desperately demanding effective therapeutic regimens. A growing body of evidence indicated that glycoprotein 130 kDa (GP130), the pivotal mediator involved in interleukin 6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, is strongly correlated with tumor progression. Therefore, GP130 could become a novel target for treating TNBC. In our earlier studies, we demonstrated bazedoxifene as being a novel GP130 inhibitor. METHODS: In the current report, anti-tumor effect of bazedoxifene on TNBC was further evaluated in TNBC cell lines SUM159, MDA-MB-231, and MDA-MB-468. We assessed anti-TNBC potency of bazedoxifene by carrying out various analysis encompassing western blot, cell proliferation, cell migration, colony formation, and growth of tumors in the xenograft mice. RESULTS: Our findings demonstrated that bazedoxifene not only decreased the expression of P-STAT3, IL-6/GP130-mediated downstream target genes P-AKT and P-ERK, but also blocked mitogen effects stimulated by IL-6, including cell viability, and overall cell survive, proliferation as well as cell migration. Likewise in laboratory animal model, tumor growth in mice was remarkably suppressed by bazedoxifene via an oral administration route. Combinational treatment of bazedoxifene plus the conventional chemotherapeutic agent, paclitaxel, synergistically impeded cell viability, colony formation, and cell migration far more significantly than the one from single-drug alone. CONCLUSIONS: Taken together, our data suggest that bazedoxifene may be developed as a promising small molecular therapeutic agent for eradicating TNBC intrinsically associated with constitutively active IL-6/GP130/STAT3 signaling cascade.
Entities:
Keywords:
Bazedoxifene; GP130; P-STAT3; Paclitaxel; Triple-negative breast cancer
Authors: Marta Ávalos-Moreno; Araceli López-Tejada; Jose L Blaya-Cánovas; Francisca E Cara-Lupiañez; Adrián González-González; Jose A Lorente; Pedro Sánchez-Rovira; Sergio Granados-Principal Journal: J Pers Med Date: 2020-10-29