Abstract
BackgroundWe have reported that the glucosamine suppressed the proliferation of the human prostate carcinoma cell line DU145 through inhibition of STAT3 signaling. DU145 cells autonomously express IL-6 and the IL-6/STAT3 signaling is activated. IL-6 receptor subunits are subject to N-glycosylation, a posttranslational modification which is important for protein stability and function. We speculated that the inhibition of STAT3 phosphorylation by glucosamine might be a functional consequence of the reduced N-glycosylation of gp130.MethodsThe human prostate cancer cell lines DU145 and PC-3 and human melanoma cell line A2058 were used in this study. Glucosamine effects on N-glycosylation of glycoproteins were determined by Western blot analysis. IL-6 binding to DU145 cells was analyzed by flow cytometry. The cell proliferation suppression was investigated by colorimetric Janus green staining method.ResultsIn DU145 cells glucosamine reduced the N-glycosylation of gp130, decreased IL-6 binding to cells and impaired the phosphorylation of JAK2, SHP2 and STAT3. Glucosamine acts in a very similar manner to tunicamycin, an inhibitor of protein N-glycosylation. Glucosamine-mediated inhibition of N-glycosylation was neither protein- nor cell-specific. Sensitivity of DU145, A2058 and PC-3 cells to glucosamine-induced inhibition of N-glycosylation were well correlated to glucosamine cytotoxicity in these cells.ConclusionOur results suggested that the glucosamine-induced global inhibition of protein N-glycosylation might be the basic mechanism underlying its multiple biochemical and cellular effects.
Highlights
We have reported that the glucosamine suppressed the proliferation of the human prostate carcinoma cell line DU145 through inhibition of STAT3 signaling
We revealed that in DU145 cells glucosamine reduced the N-glycosylation of gp130, decreased IL-6 binding to cells and impaired the phosphorylation of JAK2 on Tyr1007/1008, SHP2 on Tyr542 and STAT3 on Tyr705 residues
Glucosamine reduces the molecular mass of gp130 in DU145 cells by the inhibition of co-translational N-glycosylation To prove our hypothesis that the inhibition of STAT3 phosphorylation by glucosamine might be a functional consequence of the reduced N-glycosylation of gp130, we first studied the effect of glucosamine on the gp130 expression in DU145 cells by Western blot analysis
Summary
We have reported that the glucosamine suppressed the proliferation of the human prostate carcinoma cell line DU145 through inhibition of STAT3 signaling. We speculated that the inhibition of STAT3 phosphorylation by glucosamine might be a functional consequence of the reduced N-glycosylation of gp130. In the previous paper [1], we reported that glucosamine suppressed the proliferation and induced the death of human prostate carcinoma DU145 cells. This anti-cancer activity was associated with a decreased DNA synthesis, cell cycle arrest in G1 phase, and induction of apoptosis. In DU145 cells, IL-6 is autonomously expressed and activates the IL-6/STAT3 signaling pathway by an autocrine mechanism [8]. Janus kinases (JAKs) associated with gp130 are activated by phosphorylation and STAT3 becomes activated by the phosphorylated JAKs [9]
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