TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer

作者：Guolin Zhang, Xin Luo, Zian Wang, Jianbin Xu, Wei Zhang, Engeng Chen, Qing Meng, Di Wang, Xuefeng Huang, Wei Zhou, Zhangfa Song · 发表于：Aging · 年份：2022 · DOI：10.18632/aging.203793 · 被引用次数：29 · 研究领域：Colorectal Cancer Treatments and Studies、Peptidase Inhibition and Analysis、Cancer Treatment and Pharmacology

5-Fluorouracil (5-Fu) is the first-line chemotherapeutic option for colorectal cancer. However, its efficacy is inhibited by drug resistance. Cytokines play an important role in tumor drug resistance, even though their mechanisms are largely unknown. Using a cytokine array, we established that tissue inhibitor metalloproteinase 2 (TIMP-2) is highly expressed in 5-Fu resistant colorectal cancer patients. Analysis of samples from 84 patients showed that elevated TIMP-2 expression levels in colorectal patients were correlated with poor prognostic outcomes. In a 5-Fu-resistant patient-derived xenograft (PDX) model, TIMP-2 was also found to be highly expressed. We established an autocrine mechanism through which elevated TIMP-2 protein levels sustained colorectal cancer cell resistance to 5-Fu by constitutively activating the ERK/MAPK signaling pathway. Inhibition of TIMP-2 using an anti-TIMP-2 antibody or ERK/MAPK inhibition by U0126 suppressed TIMP-2 mediated 5-Fu-resistance in CRC patients. In conclusion, a novel TIMP-2-ERK/MAPK mediated 5-Fu resistance mechanism is involved in colorectal cancer. Therefore, targeting TIMP-2 or ERK/MAPK may provide a new strategy to overcome 5-Fu resistance in colorectal cancer chemotherapy.