ETS1 is associated with cisplatin resistance through IKKα/NF-κB pathway in cell line MDA-MB-231

Abstract

BackgroundPlatinum-based drugs are used extensively in neoadjuvant chemotherapy for triple-negative breast cancer (TNBC), but their use can be limited by resistance. In this study, we established cisplatin (DDP) resistant TNBC cells to investigate the potential relationship among ETS1, IKKα/NF-κB and resistance.MethodsThe sensitivity was evaluated by MTT, apoptosis analysis. The intracellular DDP concentration difference was tested by inductively coupled plasma mass spectrometry (ICP-MS) method. Molecular pathological mechanism of DDP resistance was explored by microarray analysis and PPI network analysis. The ETS1, NF-κB signaling change were assessed by western blot and q-PCR in vitro and vivo. The existing binds between ETS1 and the core IKKα promoter were found by luciferase assay and chromatin immunoprecipitation technique (ChIP).ResultsMDA-MB-231/DDP (231/DDP) cell had a higher IC50 value of cisplatin, lower intracellular DDP concentration, and lower apoptosis ratio than MDA-MB-231 (231/wt) cell line treated with DDP. Increased ABC transporters were induced by the activation of NF-κB pathway in 231/DDP cells. ETS1, RPL6, RBBP8, BIRC2, PIK3A and RARS were six important genes for DDP-resistance based on PPI network and expression validation. Protein expression of ETS1 and IKKα were significantly up-regulated in 231/DDP cells. However, inhibition of ETS1 expression enhances chemo-sensitivity to DDP and reversed the activation of NF-κB pathway in 231/DDP cells and subcutaneous transplantation tumor in vivo. Moreover, there is existing binds between ETS1 and the core IKKα promoter though luciferase assay and ChIP.ConclusionThis study enables us to understand the functions of ETS1 in TNBC chemotherapy and suggests that ETS1 could be used as a novel marker of poor response to DDP and a potential therapeutic target for TNBC chemotherapy.

Analysis of the Differentially Expressed Genes Induced by Cisplatin Resistance in Oral Squamous Cell Carcinomas and Their Interaction

“…Inhibition of ETS1 expression has been reported to enhance cisplatin sensitivity of resistant cell lines. ETS1 knockout increases the stability of cisplatin in mouse xenograft models (Zhang et al, 2018). These results are similar to the results obtained in the current study.…”

Targeted Inhibition of miR-221/222 Promotes Cell Sensitivity to Cisplatin in Triple-Negative Breast Cancer MDA-MB-231 Cells

“…After 7-month screening, the survived cells were stably maintained in 4 mg/mL of cisplatin. As validated, the cisplatin-resistant MDA-MB-231 cells had a higher IC 50 value of cisplatin (19.44 ± 0.89 µg/mL), compared to wild type cells (3.13 ± 0.12 µg/mL) (Zhang, 2018).…”

“…The cisplatin-resistant MDA-MB-231 cell and control were gifts from Dr. Hongfeng Chen at Shanghai University Longhua Hospital. The cisplatin-resistant MDA-MB-231 cells were obtained by discontinuously and gradually increasing dose of cisplatin as described previously (Zhang, 2018). Briefly, MDA-MB-231 wild type cells were stimulated with cisplatin of different concentrations, starting from 100 ng/ mL.…”

MCL-1 plays an oncogenic role in breast cancer by modulating chemoresistance and stemness properties by activating Wnt/β-catenin

“…However, we found that the copy number of MCL-1 in chemotherapy resistant breast cancer patients was higher than it was in sensitive patients, as shown by Foundation One CDx assays [17]. In our previous studies, we established a breast cancer cell line resistant to multiple drugs (including Taxol), MDA-MB-231/MDR (231/MDR), which has properties of cancer stem cells [18]. Herein, we demonstrate that MCL-1 is overexpressed in 231/MDR cells.…”

“…These breast cancer cells were cultured in DMEM (C11995501BT, GIBCO, USA) with 10% fetal bovine serum (FBS) (10270106, GIBCO, USA) under a humidi ed atmosphere of 37 °C and 5% CO 2 (WCI-180, Wiggens, Germany). The multidrug-resistant cell line MDA-MB-231/MDR was induced by cisplatin (MB1055, Dalian Mellon, China) by treating with a range of low to high concentrations [18].…”