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Published on: February 9, 2016
FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer
Min Xu1,2, Shuzheng Chen3, Weibin Yang1,2
1Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui, China.
Background/Aims:
Poor response to chemotherapy leads to the relapse and metastatic progression of tumors. Reprogrammed glucose metabolism is one of the important hallmarks of cancer that facilitates cancer cell survival, proliferation and chemoresistance. However, the precise fate of glucose metabolism and its role in therapy responsiveness in cancers remains largely unexplored.
Methods:
The glycolytic phenotype of doxorubicin (ADR)-resistant breast cancer cells and their parental cells was assessed by measuring glucose uptake, lactate release, and extracellular acidification rate (ECAR). Protein expression was detected by Western blotting analysis and mRNA expression was detected using q-PCR. Cell survival ratio was determined by the cell counting kit 8 assay. The role of fibroblast growth factor receptor 4 (FGFR4) in glycolysis, chemoresistance, and the underlying mechanisms were studied by using gene expression microarray and short hairpin RNA-mediated gene knockdown.
Results:
We found that glycolytic flux are increased in two doxorubicin (ADR)-resistant breast cancer cell lines compared with their parental wild type cells, as demonstrated by increased glucose uptake, lactate release, and extracellular acidification rate (ECAR). By gene expression microarray, we identified FGFR4 as a critical modulator of ADR resistance and enhanced glucose metabolism. Genetic silencing of FGFR4 increased the chemosensitivity and suppressed the enhanced glycolytic flux in ADR-resistant cells. Mechanistically, activation of FGFR4 signaling in ADR-resistant cells led to the phosphorylation of FGF receptor substrate 2 (FRS2) and further activated the downstream MAPK/ERK signaling. Pharmacological inhibition of FGFR4-FRS2-ERK signaling pathway significantly blocked the chemoresistant and glycolytic phenotypes of ADR-resistant cells.
Conclusion:
Our findings suggest that high levels of FGFR4 can increase glucose metabolism and lead to chemoresistance in breast cancer and reveal the mechanistic basis for targeting FGFR4 as a therapeutic opportunity for chemoresistant tumors.
Insights
Fibroblast growth factor receptor 4 (FGFR4) promotes chemoresistance and altered glucose metabolism in breast cancer. Targeting FGFR4 may improve treatment outcomes for chemoresistant tumors.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Chemotherapy resistance is a major cause of cancer relapse and metastasis.
- Reprogrammed glucose metabolism is a hallmark of cancer, promoting survival and chemoresistance.
- The role of glucose metabolism in therapy response remains unclear.
Purpose of the Study:
- To investigate the role of glucose metabolism in doxorubicin resistance in breast cancer.
- To identify key regulators of chemoresistance and altered glucose metabolism.
- To explore the therapeutic potential of targeting identified pathways.
Main Methods:
- Assessed glycolytic phenotype (glucose uptake, lactate release, ECAR) in resistant vs. parental cells.
- Utilized gene expression microarray and short hairpin RNA (shRNA) for gene knockdown.
- Investigated signaling pathways (FGFR4, FRS2, MAPK/ERK) using Western blotting and pharmacological inhibitors.
Main Results:
- Doxorubicin-resistant cells exhibited increased glycolytic flux.
- Fibroblast growth factor receptor 4 (FGFR4) was identified as a key modulator of resistance and glycolysis.
- FGFR4 knockdown enhanced chemosensitivity and reduced glycolysis; FGFR4 inhibition blocked chemoresistance.
Conclusions:
- Elevated FGFR4 expression drives increased glucose metabolism and chemoresistance in breast cancer.
- Targeting the FGFR4-FRS2-ERK pathway presents a therapeutic strategy for chemoresistant breast cancer.
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