Nordihydroguaiaretic acid inhibits an activated fibroblast growth factor receptor 3 mutant and blocks downstream signaling in multiple myeloma cells.
Activating mutations within fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase, are responsible for human skeletal dysplasias including achondroplasia and the neonatal lethal syndromes, Thanatophoric Dysplasia (TD) type I and II. Several of these same FGFR3 mutations have also been identified somatically in human cancers, including multiple myeloma, bladder carcinoma, and cervical cancer. Based on reports that strongly activated mutants of FGFR3 such as the TDII (K650E) mutant signal preferentially from within the secretory pathway, the inhibitory properties of nordihydroguaiartic acid (NDGA), which blocks protein transport through the Golgi, were investigated. NDGA was able to inhibit FGFR3 autophosphorylation both in vitro and in vivo. In addition, signaling molecules downstream of FGFR3 activation such as signal transducers and activators of transcription (STAT)1, STAT3, and mitogen-activated protein kinase (MAPK) were inhibited by NDGA treatment. Using HEK293 cells expressing activated FGFR3-TDII, together with several multiple myeloma cell lines expressing activated forms of FGFR3, NDGA generally resulted in a decrease in MAPK activation by 1 hour, and resulted in increased apoptosis over 24 hours. The effects of NDGA on activated FGFR3 derivatives targeted either to the plasma membrane or the cytoplasm were also examined. These results suggest that inhibitory small molecules such as NDGA that target a specific subcellular compartment may be beneficial in the inhibition of activated receptors such as FGFR3 that signal from the same compartment.
Meyer
April N
AN
Department of Chemistry and Biochemistry, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093-0367, USA.
McAndrew
Christopher W
CW
Donoghue
Daniel J
DJ
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013796:Thanatophoric Dysplasia / Q000201:enzymology / Q000235:genetics; D014162:Transfection
D016859:Lipoxygenase Inhibitors; D016222:Fibroblast Growth Factor 2; D009637:Masoprocol; D051498:Receptor, Fibroblast Growth Factor, Type 3; C063449:zileuton; D006918:Hydroxyurea
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