A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways
Journal
Cancer Research
Journal Volume
71
Journal Issue
2
Pages
473-483
Date Issued
2011-01
Author(s)
Wang, Yi-Ching
Abstract
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-OAsp is worthy for further testing as a novel antimetastasis drug for cancer treatment. ? 2011 American Association for Cancer Research.
SDGs
Other Subjects
antineoplastic agent; beta1 integrin; focal adhesion kinase; gelatinase A; gelatinase B; guanosine triphosphatase; lith o asp; paxillin; Rho guanine nucleotide binding protein; ribonuclease; sialic acid; sialyltransferase; unclassified drug; vimentin; animal experiment; animal model; antiangiogenic activity; article; cancer cell; cancer cell culture; cancer invasion; cancer patient; carcinogenesis; cell migration; cell surface; enzyme activity; human; human cell; immunoblotting; mouse; neoplasm; nonhuman; priority journal; umbilical vein endothelial cell; Animals; Cell Line; Cell Line, Tumor; Focal Adhesion Kinase 1; Humans; Integrins; Lithocholic Acid; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neovascularization, Pathologic; Paxillin; Proteomics; Sialyltransferases; Signal Transduction
Type
journal article