Knockdown of DNA‐binding protein A enhances the chemotherapy sensitivity of colorectal cancer via suppressing the Wnt/β‐catenin/Chk1 pathway

Abstract

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.

Serum exosomal hsa-circ-0004771 modulates the resistance of colorectal cancer to 5-fluorouracil via regulating miR-653/ZEB2 signaling pathway

“…5 - FU-resistant SW620 cells (SW620-R) were generated by continuously exposing the cells to an increasing concentration gradient of 5-FU (#F6627, 10–200 μM, Sigma-Aldrich) and cultured in Dulbecco’s Modified Eagle’s Medium (DMEM, # 12800017, Invitrogen, Carlsbad, CA, USA) containing 10% fetal bovine serum (FBS, #26400044, Invitrogen, USA), 1% penicillin/streptomycin ( # 15070063, Gibco, BRL) at 37℃ in a humidified incubator with 5% CO2 based on the recent report in 2020 [ 32 ]. 5-FU-resistant HCT116 cells (HCT116-R) were established by treating them with gradually increasing concentrations of 5-FU (#F6627, 5 μM to 50 μM, Sigma-Aldrich) for 9 months and were maintained in Iscove’s modified Dulbecco’s medium (IMDM, # 12440–053, Invitrogen, Carlsbad, CA, USA) with 10% FBS (#26400044, Invitrogen, USA) and 1% penicillin and streptomycin ( # 15070063, Gibco, BRL), in a humidified incubator (5% CO2) at 37℃, as previously described [ 33 ].…”

Prediction of DNA-Binding Protein–Drug-Binding Sites Using Residue Interaction Networks and Sequence Feature

“…Another research has found DNA-binding protein A (dbpA) may be a new and effective therapeutic target, which is useful for colorectal cancer (CRC). The downregulation of dbpA is a pivotal method to inhibit cell proliferation and induce cell apoptosis as well as cell cycle arrest in cancer cells because it can not only restrict the growth of tumor but also improve the drug sensitivity of CRC cells in vivo ( Tong et al, 2020 ). These studies have shown that DNA-binding proteins exist in living cells widely and participate in many cell activities.…”