A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin-mediated signaling.
Aberrant sialylation catalyzed by sialyltransferases (STs) is frequently found in cancer cells and is associated with increased cancer metastasis. However, ST inhibitors developed till now are not applicable for clinical use because of their poor cell permeability. In this study, a novel ST inhibitor AL10 derived from the lead compound lithocholic acid identified in our previous study is synthesized and the anti-cancer effect of this compound is studied. AL10 is cell-permeable and effectively attenuates total sialylation on cell surface. This inhibitor shows no cytotoxicity but inhibits adhesion, migration, actin polymerization and invasion of alpha-2,3-ST-overexpressing A549 and CL1.5 human lung cells. Inhibition of adhesion and migration by AL10 is associated with reduced sialylation of various integrin molecules and attenuated activation of the integrin downstream signaling mediator focal adhesion kinase. More importantly, AL10 significantly suppresses experimental lung metastasis in vivo without affecting liver and kidney function of experimental animals as determined by serum biochemical assays. Taken together, AL10 is the first ST inhibitor, which exhibits potent anti-metastatic activity in vivo and may be useful for clinical cancer treatment.
Chiang
Chi-Hsiang
CH
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Wang
Chie-Hong
CH
Chang
Hui-Chiu
HC
More
Shivaji V
SV
Li
Wen-Shan
WS
Hung
Wen-Chun
WC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000503:physiopathology / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics; D012799:Sialyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
C549106:AL-10 compound; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006017:Glycolipids; D016023:Integrins; D008562:Membrane Glycoproteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C465036:Rbfox1 protein, mouse; D008095:Lithocholic Acid; D012799:Sialyltransferases; D019158:N-Acetylneuraminic Acid