Holothurian Glycosaminoglycan Inhibits Metastasis and Thrombosis via Targeting of Nuclear Factor-κB/Tissue Factor/Factor Xa Pathway in Melanoma B16F10 Cells

Abstract

Holothurian glycosaminoglycan (hGAG) is a high-molecular-weight form of fucosylated chondroitin sulfate and has an antithrombotic effect. Our previous studies demonstrated that hGAG efficiently inhibited tumor cell metastasis. The interplays between thrombosis and tumor progression may have a major impact on hematogenous metastasis. In this study, we demonstrated that the mouse melanoma B16F10 cells treated with hGAG displayed a significant reduction of metastasis and coagulation capacity in vitro and in vivo. Mechanistic studies revealed that hGAG treatment in B16F10 cells remarkably inhibited the formation of fibrin through attenuating the generation of activated Factor Xa (FXa), without affecting the expression of urokinase (uPA) and plasminogen activator inhibitor 1 (PAI-1) that involved in fibrinolysis. Moreover, hGAG treatment downregulated the transcription and protein expression of tissue factor (TF). Promoter deletions, site mutations and functional studies identified that the nuclear transcription factor NF-κB binding region is responsible for hGAG-induced inhibition of TF expression. While the hGAG treatment of B16F10 cells was unable to inhibit NF-κB expression and phosphorylation, hGAG significantly prevented nuclear translocation of NF-κB from the cytosol, a potential mechanism underlying the transcriptional suppression of TF. Moreover, hGAG markedly suppressed the activation of p38MAPK and ERK1/2 signaling pathways, the central regulators for the expression of metastasis-related matrix metalloproteinases (MMPs). Consequently, hGAG exerts a dual function in the inhibition of metastasis and coagulation activity in mouse melanoma B16F10 cells. Our studies suggest hGAG to be a promising therapeutic agent for metastatic cancer treatment.

Anti-cancer Effects of CME-1, a Novel Polysaccharide, Purified from the Mycelia of Cordyceps sinensis against B16-F10 Melanoma Cells

“…[39] A recent study established that holothurian glycosaminoglycan inhibited metastasis and thrombosis via targeting of NF-κB pathway in melanoma B16F10 cells. [40] So also, in the present study a significant recovery of the degradation of IkBα by CME-1, may provide a molecular basis underlying the CME-1-mediated inhibition of MMP-1 via inhibition of IkBα degradation in B16 melanoma cells.…”

Absence of tissue factor is characteristic of lymphoid malignancies of both T- and B-cell origin

“…This fact is relevant, since targeting tumor-associated TF as is currently proposed for solid tumors (through the use of immuno-conjugates, anti-TF antibodies, TF pathway inhibitors, targeted photodynamic therapy, and microRNAs), may not be useful in lymphoid neoplasias [4,28,29]. This does not rule out however, a role for TF from non-neoplastic cell sources (activated endothelium, platelets and or monocytes) as a result of host response to cancer or its treatment, in the development of thrombosis or in the induction of malignant tumor behavior [30].…”

Chondroitin Sulfate-Degrading Enzymes as Tools for the Development of New Pharmaceuticals

“…Fucosylated CSs (fCSs) are CSs with fucose branches invariably extending from the 3-O-position of the GlcA. These have demonstrated anticoagulant and antithrombotic activities as substitutes for heparin [107] and have attracted considerable attention as potential antitumor drugs [108,109] and for their application as a treatment of hyperlipidemia [110,111]. Unfortunately, native fCSs can also cause side effects such as the activation of FXII, platelet aggregation [112], hypertension and spontaneous bleeding in humans [87], limiting their therapeutic applications.…”