Increased
sialyltransferase (ST) activity promotes
cancer cell
metastasis, and overexpression of cell surface
sialic acid correlates with poor prognosis in
cancer patients. To seek
therapies targeting
metastasis for
cancer treatment, we developed a novel ST inhibitor, Lith-O-Asp, and investigated its antimetastatic and antiangiogenic effects and mechanisms. We found that cells treated with Lith-O-Asp showed a reduction of activity on various ST
enzymes by in vitro and cell-based activity analyses. Lith-O-Asp inhibited migration and invasion abilities in various
cancer cell lines and showed inhibitory effect on the angiogenic activity of human umbilical vein endothelial cells. Indeed, Lith-O-Asp treatment consequently delayed
cancer cell
metastasis in experimental and spontaneous
metastasis assays in animal models. Importantly, Lith-O-Asp decreased the
sialic acid modification of integrin-β1 and inhibited the expression of phospho-FAK, phospho-
paxillin, and the matrix
metalloprotease (
MMP) 2 and MMP9. Lith-O-Asp attenuated the
Rho GTPase activity leading to actin dynamic impairment. In addition, 2DE-MS/MS and immunoblotting analyses showed that Lith-O-Asp altered the
protein expression level and phosphorylation status of various
proteins involved in crucial
metastasis and angiogenesis pathways such as
vimentin and
ribonuclease/angiogenin inhibitor RNH1. Furthermore, Lith-O-Asp treatment significantly inhibited the invasive ability exerted by ectopic overexpression of various ST
enzymes catalyzing α-2,6- or α-2,3-sialylation. Our results provide compelling evidence that the potential pan-ST inhibitor, Lith-O-Asp, suppressed
cancer cell
metastasis likely by inhibiting FAK/
paxillin signaling and expressing antiangiogenesis factors. Lith-O-Asp is worthy for further testing as a novel antimetastasis
drug for
cancer treatment.