Resistance to chemotherapy is associated with fibroblast growth factor receptor 4 up-regulation.
OBJECTIVE
Establishment of antiapoptotic signaling pathways in tumor cells is a major cause for the failure of chemotherapy against cancer. To investigate the underlying mechanisms, we developed an experimental approach that is based on the genetic plasticity of cancer cells and the selection for cell survival on treatment with chemotherapeutic agents.


METHODS
Gene expression changes of surviving cell clones were analyzed by macroarrays. Involvement of fibroblast growth factor receptor 4 (FGFR4) in antiapoptotic pathways was elucidated by apoptosis assays, small interfering RNA experiments, and an antagonistic antibody.


RESULTS
We show that FGFR4 gene expression is up-regulated in doxorubicin-treated, apoptosis-resistant cancer cell clones. Ectopic expression of FGFR4 in cancer cells led to reduced apoptosis sensitivity on treatment with doxorubicin or cyclophosphamide, whereas knockdown of endogenous FGFR4 expression in breast cancer cell lines had the opposite effect. FGFR4 overexpression resulted in Bcl-xl up-regulation at both mRNA and protein levels. Knockdown of FGFR4 expression by small interfering RNA caused a decrease in phospho-extracellular signal-regulated kinase 1/2 levels and reduced Bcl-xl expression. Moreover, an antagonistic FGFR4 antibody suppressed the resistance of cancer cells with endogenous FGFR4 expression against apoptosis-inducing chemotherapeutic agents.


CONCLUSIONS
Based on these findings, we propose an antiapoptotic signaling pathway that is initiated by FGFR4 and regulating the expression of Bcl-xl through the mitogen-activated protein kinase cascade. Our findings are exemplary for a novel strategy toward the elucidation of diverse signaling pathways that define antiapoptotic potential in cancer cells. These observations open new avenues toward the diagnosis of chemoresistant tumors and therapies targeting FGFR4-overexpressing cancers.
Roidl
Andreas
A
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Berger
Hans-Jürgen
HJ
Kumar
Sushil
S
Bange
Johannes
J
Knyazev
Pjotr
P
Ullrich
Axel
A
D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors; D006801:Humans; D020935:MAP Kinase Signaling System; D012333:RNA, Messenger / Q000032:analysis; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D015854:Up-Regulation; D051020:bcl-X Protein / Q000032:analysis
C494811:BCL2L1 protein, human; C117476:FGF19 protein, human; D012333:RNA, Messenger; D051020:bcl-X Protein; D005346:Fibroblast Growth Factors; D004317:Doxorubicin; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4