title: A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways.
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-O-Asp is worthy for further testing as a novel antimetastasis drug for cancer treatment.
authors.affiliation: Institute of Basic Medical Science and Department of Chemistry, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jia-Yang
authors.initials: JY
authors.lastname: Chen
authors.forename: Yen-An
authors.initials: YA
authors.lastname: Tang
authors.forename: Sin-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Hsueh-Fen
authors.initials: HF
authors.lastname: Juan
authors.forename: Li-Wha
authors.initials: LW
authors.lastname: Wu
authors.forename: Ying-Chieh
authors.initials: YC
authors.lastname: Sun
authors.forename: Szu-Chi
authors.initials: SC
authors.lastname: Wang
authors.forename: Kuan-Wei
authors.initials: KW
authors.lastname: Wu
authors.forename: Gopula
authors.initials: G
authors.lastname: Balraj
authors.forename: Tzu-Ting
authors.initials: TT
authors.lastname: Chang
authors.forename: Wen-Shan
authors.initials: WS
authors.lastname: Li
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Cheng
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D051419:Paxillin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040901:Proteomics; D012799:Sialyltransferases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016023:Integrins; D051419:Paxillin; D008095:Lithocholic Acid; D012799:Sialyltransferases; D051417:Focal Adhesion Kinase 1