Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway
| Autor: | Zhanyu Wang, Rulu Pan, Wenyi Zhang, Ziqi Lin, Shuyi Chong, Xincheng Lu, Liting Lu, Qian Zhang, Mei Lu, Huan Lin, Yuan Qin, Siqing Gong, Liao Wanqin |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research Colorectal cancer Drug resistance Lipocalin Biology Epigenesis Genetic Mice Downregulation and upregulation Lipocalin-2 Cell Line Tumor Genetics medicine Animals Humans Epigenetics Promoter Regions Genetic Molecular Biology Protein kinase B Protein Stability Integrin beta3 NF-kappa B DNA Methylation medicine.disease Prognosis Up-Regulation Gene Expression Regulation Neoplastic src-Family Kinases Cell culture Drug Resistance Neoplasm Cancer research Fluorouracil Colorectal Neoplasms HT29 Cells Neoplasm Transplantation Proto-oncogene tyrosine-protein kinase Src Signal Transduction |
| Zdroj: | Oncogene. 40(45) |
| ISSN: | 1476-5594 |
| Popis: | The therapeutic efficacy of 5-fluorouracil (5-FU) is often reduced by the development of drug resistance. We observed significant upregulation of lipocalin 2 (LCN2) expression in a newly established 5-FU-resistant colorectal cancer (CRC) cell line. In this study, we demonstrated that 5-FU-treated CRC cells developed resistance through LCN2 upregulation caused by LCN2 promoter demethylation and that feedback between LCN2 and NF-κB further amplified LCN2 expression. High LCN2 expression was associated with poor prognosis in CRC patients. LCN2 attenuated the cytotoxicity of 5-FU by activating the SRC/AKT/ERK-mediated antiapoptotic program. Mechanistically, the LCN2-integrin β3 interaction enhanced integrin β3 stability, thus recruiting SRC to the cytomembrane for autoactivation, leading to downstream AKT/ERK cascade activation. Targeting LCN2 or SRC compromised the growth of CRC cells with LCN2-induced 5-FU resistance. Our findings demonstrate a novel mechanism of acquired resistance to 5-FU, suggesting that LCN2 can be used as a biomarker and/or therapeutic target for advanced CRC. |
| Databáze: | OpenAIRE |
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