Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway

• Published in: Oncogene 2021-11, Vol.40 (45), p.6369-6380
• Main Authors: Zhang, Wenyi, Pan, Rulu, Lu, Mei, Zhang, Qian, Lin, Ziqi, Qin, Yuan, Wang, Zhanyu, Gong, Siqing, Lin, Huan, Chong, Shuyi, Lu, Liting, Liao, Wanqin, Lu, Xincheng
• Format: Article
• Language: English
• Subjects: 13/1; 13/105; 13/2; 13/31; 13/95; 14/19; 38/109; 38/39; 38/77; 38/90; 5-Fluorouracil; 631/67/1059/2326; 631/67/395; 64/60; 82/29; 82/51; AKT protein; Animals; Apoptosis; Cell Biology; Cell Line, Tumor; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cytotoxicity; Demethylation; DNA Methylation - drug effects; Drug resistance; Drug Resistance, Neoplasm; Epigenesis, Genetic - drug effects; Epigenetics; Fluorouracil - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; HT29 Cells; Human Genetics; Humans; Integrin beta3 - chemistry; Integrin beta3 - metabolism; Internal Medicine; Lipocalin; Lipocalin-2 - genetics; Lipocalin-2 - metabolism; Male; Medicine; Medicine & Public Health; Mice; Neoplasm Transplantation; NF-kappa B - metabolism; NF-κB protein; Oncology; Prognosis; Promoter Regions, Genetic - drug effects; Protein Stability; Signal Transduction - drug effects; src-Family Kinases - metabolism; Up-Regulation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-02029-4

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.