Tong Cong, Qu Kai, Wang Guorong, Liu Ruiting, Duan Baojun, Wang Xiaoqiang, Liu Chang
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
First Department of General Surgery, Shaanxi Provincial People's Hospital/The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China.
Cell Biol Int. 2020 Oct;44(10):2075-2085. doi: 10.1002/cbin.11416. Epub 2020 Jul 31.
DNA-binding protein A (dbpA) is reported to be upregulated in many cancers and associated with tumor progress. The present study aimed to investigate the role of dbpA in 5-fluorouracil (5-FU)-resistant and oxaliplatin (L-OHP)-resistant colorectal cancer (CRC) cells. We found that 5-FU and L-OPH treatment promoted the expression of dbpA. Enhanced dbpA promoted the drug resistance of SW620 cells to 5-FU and L-OHP. DbpA knockdown inhibited cell proliferation, induced cell apoptosis, and cell cycle arrested in SW620/5-FU and SW620/L-OHP cells. Besides, dbpA short hairpin RNA (shRNA) enhanced the cytotoxicity of 5-FU and L-OHP to SW620/5-FU and SW620/L-OHP cells. Meanwhile, dbpA shRNA inhibited the activation of the Wnt/β-catenin pathway that induced by 5-FU stimulation in SW620/5-FU cells. Activation of the Wnt/β-catenin pathway or overexpression of checkpoint kinase 1 (Chk1) abrogated the promoting effect of dbpA downregulation on 5-FU sensitivity of CRC cells. Importantly, downregulation of dbpA suppressed tumor growth and promoted CRC cells sensitivity to 5-FU in vivo. Our study indicated that the knockdown of dbpA enhanced the sensitivity of CRC cells to 5-FU via Wnt/β-catenin/Chk1 pathway, and DbpA may be a potential therapeutic target to sensitize drug resistance CRC to 5-FU and L-OHP.
据报道，DNA结合蛋白A（dbpA）在许多癌症中上调，并与肿瘤进展相关。本研究旨在探讨dbpA在5-氟尿嘧啶（5-FU）耐药和奥沙利铂（L-OHP）耐药的结直肠癌（CRC）细胞中的作用。我们发现5-FU和L-OPH处理可促进dbpA的表达。dbpA表达增强促进了SW620细胞对5-FU和L-OHP的耐药性。敲低DbpA可抑制SW620/5-FU和SW620/L-OHP细胞的增殖，诱导细胞凋亡，并使细胞周期停滞。此外，dbpA短发夹RNA（shRNA）增强了5-FU和L-OHP对SW620/5-FU和SW620/L-OHP细胞的细胞毒性。同时，dbpA shRNA抑制了SW620/5-FU细胞中由5-FU刺激诱导的Wnt/β-连环蛋白信号通路的激活。Wnt/β-连环蛋白信号通路的激活或检查点激酶1（Chk1）的过表达消除了dbpA下调对CRC细胞5-FU敏感性的促进作用。重要的是，dbpA的下调在体内抑制了肿瘤生长并提高了CRC细胞对5-FU的敏感性。我们的研究表明，敲低dbpA通过Wnt/β-连环蛋白/Chk1信号通路增强了CRC细胞对5-FU的敏感性，并且DbpA可能是使耐药性CRC对5-FU和L-OHP敏感的潜在治疗靶点。
