Reversal of basic fibroblast growth factor-mediated autocrine cell transformation by aromatic anionic compounds.
NIH-3T3 cells transfected with basic fibroblast growth factor (bFGF) fused to a signal peptide sequence (spbFGF cells) are transformed in vitro and tumorigenic in vivo. Treatment of spbFGF cells with low and nontoxic concentrations (0.5-2.5 micrograms/ml) of negatively charged, nonsulfated aromatic compounds (e.g., aurin tricarboxylic acid, 4-hydroxyphenoxyacetic acid) resulted in restoration of their normal proliferative rate, morphological appearance, and adhesion properties. Binding and cross-linking experiments using 125I-labeled bFGF revealed that these alterations were associated with an up-regulation of high affinity receptors bFGF receptors was induced by these compounds in spbFGF cells that were seeded on fibronectin to enforce a firm cell attachment and flattening. Thus, induction of spbFGF cell adhesion and spreading may not be related to restoration of normal bFGF-receptor interactions. Although the negatively charged aromatic compounds mimic many of the effects of heparin in other systems (e.g., release of heparin- and heparan sulfate-bound proteins, inhibition of heparanase), heparin, heparan sulfate, and dextran sulfate were not effective at the low concentrations of the anionic compounds used in the present study. Likewise, suramin, a sulfated aromatic molecule, was effective at toxic concentrations, 400-600-fold higher than the nonsulfated aromatic compounds. The development of defined, nontoxic anionic compounds may provide a new strategy to interfere with the autonomous and anchorage independent mode of cell growth involved in autocrine cell transformation and cancer.
Benezra
M
M
Department of Oncology, Hadassah University Hospital, Jerusalem, Israel.
Vlodavsky
I
I
Yayon
A
A
Bar-Shavit
R
R
Regan
J
J
Chang
M
M
Ben-Sasson
S
S
D016475:3T3 Cells; D000818:Animals; D000838:Anions / Q000494:pharmacology; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects* / Q000235:genetics / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D006838:Hydrocarbons / Q000494:pharmacology*; D051379:Mice; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000838:Anions; D006131:Growth Inhibitors; D006838:Hydrocarbons; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D001312:Aurintricarboxylic Acid