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Blocking IL-6/GP130 Signaling Inhibits Cell Viability/Proliferation, Glycolysis, and Colony Forming Activity in Human Pancreatic Cancer Cells

[ Vol. 18 , Issue. ]

Author(s):

Xiang Chen, Jilai Tian, Gloria H. Su and Jiayuh Lin*Pages 1-11 (11)

Abstract:


Background: Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunctions of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance. Objective: We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer. Method: The effects on cell viability and cell proliferation were measured by MTT and BrdU assays, respectively. The effects on glycolysis was determined by cell-based assays to measure lactate levels. Protein expression changes were evaluated by western blotting and immunoprecipitation. SiRNA transfection was used to knock down estrogen receptor α gene expression. Colony forming ability was determined by colony forming cell assay. Results: We demonstrated that IL-6 can induce pancreatic cancer cell viability/proliferation and glycolysis. We also showed that a repurposing FDA-approved drug bazedoxifene could inhibit the IL-6/IL-6R/GP130 complexes. Bazedoxifene also inhibited JAK1 binding to IL-6/IL-6R/GP130 complexes and STAT3 phosphorylation. In addition, bazedoxifene inhibited IL-6 mediated cell viability/ proliferation and glycolysis in pancreatic cancer cells. Consistently, other IL-6/GP130 inhibitors SC144 and evista showed similar inhibition of IL-6 stimulated cell viability, cell proliferation and glycolysis. Furthermore, all three IL-6/GP130 inhibitors reduced the colony forming ability of pancreatic cancer cells. Conclusion: Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors

Keywords:

IL-6/GP130 signaling, bazedoxifene, pancreatic cancer, cell viability, cell proliferation, glycolysis, colony forming

Affiliation:

Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201



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