Blocking IL-6/GP130 signaling inhibits cell viability/proliferation, glycolysis, and colony forming activity in human pancreatic cancer cells.

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Blocking IL-6/GP130 signaling inhibits cell viability/proliferation, glycolysis, and colony forming activity in human pancreatic cancer cells.

Curr Cancer Drug Targets. 2018 Apr 30;:

Authors: Chen X, Tian J, Su GH, Lin J

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.

PMID: 29714141 [PubMed - as supplied by publisher]

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