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FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-kappaB.

ABSTRACT: Quinacrine, a drug with antimalarial and anticancer activities that inhibits NF-?B and activates p53, has progressed into phase II clinical trials in cancer. To further elucidate its mechanism of action and identify pathways of drug resistance, we used an unbiased method for validation-based insertional mutagenesis to isolate a quinacrine-resistant cell line in which an inserted CMV promoter drives overexpression of the FER tyrosine kinase (FER). Overexpression of FER from a cDNA confers quinacrine resistance to several different types of cancer cell lines. We show that quinacrine kills cancer cells primarily by inhibiting the activation of NF-?B and that increased activation of NF-?B through FER overexpression mediates resistance. EGF activates NF-?B and stimulates phosphorylation of FER, EGF receptor (EGFR), and ERK p42/p44, and decreased expression of FER or inhibition of ERK phosphorylation inhibits the EGF-induced activation of NF-?B. FER binds to EGFR, and overexpression of FER in cells untreated with EGF increases this association, leading to increased phosphorylation of EGFR and ERK. We conclude that FER is on a pathway connecting EGFR to NF-?B activation and that this function is responsible for FER-dependent resistance to quinacrine.

SUBMITTER: Guo C

PROVIDER: S-EPMC3093511 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-kappaB.

Guo Canhui C Stark George R GR

Proceedings of the National Academy of Sciences of the United States of America 20110425 19

Quinacrine, a drug with antimalarial and anticancer activities that inhibits NF-κB and activates p53, has progressed into phase II clinical trials in cancer. To further elucidate its mechanism of action and identify pathways of drug resistance, we used an unbiased method for validation-based insertional mutagenesis to isolate a quinacrine-resistant cell line in which an inserted CMV promoter drives overexpression of the FER tyrosine kinase (FER). Overexpression of FER from a cDNA confers quinacr ...[more]

PMID: 21518868

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Project description:NF?B signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NF?B activation has not been previously described, although FGFs have been known to antagonize TNF?-induced apoptosis.Here, we demonstrate an interaction between FGFR4 and IKK? (Inhibitor of NF?B Kinase ? subunit), an essential component in the NF?B pathway. This novel interaction was identified utilizing a yeast two-hybrid screen [1] and confirmed by coimmunoprecipitation and mass spectrometry analysis. We demonstrate tyrosine phosphorylation of IKK? in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNF? (Tumor Necrosis Factor ?) to activate NF?B pathways, FGFR4 activation results in significant inhibition of NF?B signaling as measured by decreased nuclear NF?B localization, by reduced NF?B transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKK? kinase activity towards the substrate GST-I?B? in in vitro assays. FGF19 stimulation of endogenous FGFR4 in TNF?-treated DU145 prostate cancer cells also leads to a decrease in IKK? activity, concomitant reduction in NF?B nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNF? treatment of DU145 cells, in comparison with TNF? alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NF?B signaling.These results identify a compelling link between FGFR4 signaling and the NF?B pathway, and reveal that FGFR4 activation leads to a negative effect on NF?B signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NF?B signaling will not be limited to FGFR4 alone.

Dataset Information

FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-kappaB.

Publications

FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-kappaB.

Similar Datasets

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