Abstract
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. 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. 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. 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.
Highlights
Establishment of antiapoptotic signaling pathways in tumor cells is a major cause for the failure of chemotherapy against cancer.Toinvestigate the underlying mechanisms, we developed an experimentalapproach that is basedonthe genetic plasticity of cancer cells and the selectionfor cell survival on treatment with chemotherapeutic agents
We show that doxorubicinresistant cancer cells become sensitive after being treated with small interfering RNA or a blocking antibody against fibroblast growth factor receptor 4 (FGFR4)
Only with cyclophosphamide reduced apoptosis sensitivity was Resistance of MDA-MB-453 breast cancer cells to doxorubicin correlates with FGFR4 up-regulation
Summary
Establishment of antiapoptotic signaling pathways in tumor cells is a major cause for the failure of chemotherapy against cancer.Toinvestigate the underlying mechanisms, we developed an experimentalapproach that is basedonthe genetic plasticity of cancer cells and the selectionfor cell survival on treatment with chemotherapeutic agents. Subsequent comparison of gene expression profiles of apoptosis-sensitive breast cancer cells and corresponding apoptosis-resistant clones led to the identification of fibroblast growth factor receptor 4 (FGFR4) as a gene with increased gene expression in response to treatment with doxorubicin or cyclophosphamide. In a combined application of FGFR4-blocking antibody and the chemotherapeutic drug doxorubicin, we could further increase the apoptosis rate of cancer cell lines, suggesting a combinatorial strategy of FGFR4 inhibitors (e.g., antagonistic antibodies) and chemotherapeutic drugs in FGFR4-overexpressing cancers. These results present new options toward the early diagnosis of chemoresistance and suggest novel combinations of chemotherapy and antiFGFR4 agents to prevent or significantly delay the onset of therapy resistance
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
