Role of galectin-3 in breast cancer metastasis: involvement of nitric oxide.
We investigated the role of galectin-3 in metastasis of human breast carcinoma BT549 cells using the experimental liver metastasis model. Underlying mechanisms were then elucidated using the liver/tumor co-culture and cell culture systems. After intrasplenic injection, galectin-3 cDNA transfected BT549 cells (BT549(gal-3 wt)) formed metastatic colonies in the liver, while galectin-3 null BT549 cells (BT549(par)) did not, demonstrating that galectin-3 enhances metastatic potential. More than 90% of BT549(gal-3 wt) cells survived after 24 hours-co-culture with the liver fragments isolated following ischemia treatment. In contrast, more than half of BT549(par) cells showed metabolic death following co-culture with the liver fragments. When the liver from inducible nitric oxide synthase (iNOS) knockout mice was used, no cytotoxicity to BT549(par) cells was observed. Thus, iNOS exerts cytotoxicity on BT549(par) cells and galectin-3 can protect against iNOS-induced cytotoxicity. BT549(gal-3 wt) also exhibited enhanced survival against peroxynitrite (up to 400 micromol/L) in vitro. A single mutation in the NWGR motif of galectin-3 obliterated both metastatic capability and cell survival, indicating that the antiapoptotic function of galectin-3 is involved in enhanced metastasis. In conclusion, galectin-3 enhances the metastatic potential of BT549 cells through resistance to the products of iNOS, possibly through its bcl-2-like antiapoptotic function.
Song
Young K
YK
Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Billiar
Timothy R
TR
Lee
Yong J
YJ
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival / Q000235:genetics; D005260:Female; D037502:Galectin 3; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D014162:Transfection
D000943:Antigens, Differentiation; D037502:Galectin 3; D008562:Membrane Glycoproteins; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse