Autocrine growth factor regulation of lysyl oxidase expression in transformed fibroblasts.
Lysyl oxidase catalyzes oxidative deamination of peptidyl-lysine and hydroxylysine residues in collagens and lysine residues in elastin to form peptidyl aldehydes that are required for the formation of covalent cross-links in normal extracellular matrix biosynthesis. Lysyl oxidase in addition has tumor suppressor activity, and phenotypic reversion of transformed cell lines is accompanied by increased lysyl oxidase expression. The mechanism of low expression of lysyl oxidase in tumor cells is unknown. The present study investigates the hypothesis that autocrine growth factor pathways maintain low lysyl oxidase expression levels in c-H-ras-transformed fibroblasts (RS485 cell line). Autocrine pathways were blocked with suramin, a general inhibitor of growth factor receptor binding, and resulted in more than a 10-fold increase in lysyl oxidase expression and proenzyme production. This regulation was found to be reversible and occurred at the transcriptional level determined using lysyl oxidase promoter/reporter gene assays. Function blocking anti-fibroblast growth factor-2 (FGF-2) antibody enhanced lysyl oxidase expression in the absence of suramin. Finally, the addition of FGF-2 to suramin-treated cells completely reversed suramin stimulation of lysyl oxidase mRNA levels. Data support that an FGF-2 autocrine pathway inhibits lysyl oxidase transcription in the tumorigenic-transformed RS485 cell line. This finding may be of therapeutic significance and, in addition, provides a new experimental approach to investigate the mechanism of the tumor suppressor activity of lysyl oxidase.
Palamakumbura
Amitha H
AH
Boston University Goldman School of Dental Medicine, Division of Oral Biology, Boston, Massachusetts 02118, USA.
Sommer
Pascal
P
Trackman
Philip C
PC
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D011905:Genes, ras; D008156:Luciferases; D051379:Mice; D011401:Promoter Regions, Genetic; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D013498:Suramin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D013498:Suramin; D008156:Luciferases; D008249:Protein-Lysine 6-Oxidase