Farnesyltransferase inhibitor FTI-277 prevents autocrine growth stimulation of neuroblastoma by BDNF.
OBJECTIVE
Autocrine growth stimulation by IGF-II and BDNF is frequently observed in neuroblastoma. The signals of the receptors of these growth factors are transduced to the nucleus via the Ras-MAP-kinase pathway where they induce proliferation. Inactivation of Ras-proteins by farnesyltransferase inhibitors such as FTI-277 disrupts growth stimulation of ras-transformed cells. We investigated whether FTI-277 is also active against tumor cells with constitutively activated growth factor receptors but lacking ras-mutations.


METHODS
We analyzed eight different neuroblastoma cell lines for the expression of BDNF and its receptor trkB. Two of these cell lines with a complete autocrine BDNF loop were treated with FTI-277, and the effects of Ras-inactivation on the signal transduction of BDNF were analyzed.


RESULTS
Treatment of neuroblastoma cells with 10 microM FTI-277 for 4 days reduced the amount of membrane-bound Ras-protein to almost 50%. Activation of MAP-kinase, induction of N-myc expression, and proliferation were clearly reduced in the treated cells. In addition, we observed some cytotoxic effects of FTI-277 accompanied by morphological changes of the neuroblastoma cells and a delayed induction of apoptosis.


CONCLUSIONS
Farnesyltransferase inhibitors are active against neuroblastoma cells but the mechanism of action is not limited to inactivation of Ras. Further investigations on the targets of FTI-277 are recommended.
Girgert
Rainer
R
Department of Gynecology and Obstetrics, University of Ulm, Prittwitzstrasse 43, 89075, Ulm, Germany. rainer.girgert@medizin.uni-ulm.de
Wittrock
Josefa
J
Pfister
Sabine
S
Schweizer
Paul
P
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D016259:Genes, myc; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D020813:Receptor, trkB / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; C096856:FTI 277; D012333:RNA, Messenger; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D020813:Receptor, trkB; D018631:ras Proteins