Downregulation of STAT3, β-Catenin, and Notch-1 by Single and Combinations of siRNA Treatment Enhance Chemosensitivity of Wild Type and Doxorubicin Resistant MCF7 Breast Cancer Cells to Doxorubicin

Abstract

Combinatorial therapeutic strategies using siRNA and small molecules to eradicate tumors are emerging. Targeting multiple signaling pathways decreases the chances of cancer cells switching and adapting new signaling processes that may occur when using a single therapeutic modality. Aberrant functioning of Notch-1, Wnt/β-catenin, and STAT3 proteins and their crosstalk signaling pathways have been found to be involved in tumor survival, drug resistance, and relapse. In the current study, we describe a therapeutic potential of single and combinations of siRNA designed for silencing Notch-1, Wnt/β-catenin, and STAT3 in MCF7_DoxS (wild type) and MCF7_DoxR (doxorubicin resistant) breast cancer cells. The MCF7_DoxR cells were developed through treatment with a gradual increase in doxorubicin concentration, the expression of targeted genes was investigated, and the expression profiling of CD44/CD24 of the MCF7_DoxS and MCF7_DoxR cells were detected by flow cytometry. Both MCF7_DoxS and MCF7_DoxR breast cancer cells were treated with single and combinations of siRNA to investigate synergism and were analyzed for their effect on cell proliferation with and without doxorubicin treatment. The finding of this study showed the overexpression of targeted genes and the enrichment of the CD44−/CD24+ phenotype in MCF7_DoxR cells when compared to MCF7_DoxS cells. In both cell lines, the gene silencing efficacy showed a synergistic effect when combining STAT3/Notch-1 and STAT3/Notch-1/β-catenin siRNA. Interestingly, the chemosensitivity of MCF7_DoxS and MCF7_DoxR cells to doxorubicin was increased when combined with siRNA treatment. Our study shows the possibility of using single and combinations of siRNA to enhance the chemosensitivity of cancer cells to conventional antitumor chemotherapy.

The Tetramethylpyrazine Derivative Statmp-151: A Novel Small Molecule Stat3 Inhibitor With Promising Activity Against Breast Cancer

“…Accumulating evidence has shown that Stat3 signalling is involved in breast cancer initiation and progression. Inhibition of the activity of Stat3 has become a popular therapeutic strategy (Zhang et al, 2010;Li et al, 2011;Alshaer et al, 2019;Xie et al, 2019). Therefore, the aim of this study was to explore the mechanisms of a novel small molecule inhibitor, Statmp-151, in breast cancer cells and provide support for the treatment of breast cancer.…”

“…Stattic is one of the classic inhibitors of Stat3 but is limited by low activity, low selectivity and high toxicity (Zhang et al, 2010). Ligustrazine is an alkaloid found in nature whose structure is simple and easy to modify (Alshaer et al, 2019;Xie et al, 2019). Ligustrazine has good pharmacokinetic properties, fast absorption, broad distribution and no cumulative toxicity (Cheng et al, 2007;Wu et al, 2013;Zeng et al, 2013;Han et al, 2015).…”

<p>Effect of miR-515-5p on Proliferation and Drug Sensitivity of Retinoblastoma Cells</p>

“…Notch1 was reported to involve in the malignant phenotype of RB 12,31 and chemosensitivity of multiple tumors. [32][33][34][35][36] The results of RT-qPCR and Western blot showed that Notch1 was significantly upregulated in RB cells (p < 0.05) ( Figure 1A and B). However, the upstream miR regulating Notch1 expression remained unclear.…”

Mechanisms of tRNA-derived fragments and tRNA halves in cancer treatment resistance

“…The FZD3 protein is mapped to chromosome 8p21, a major component of the Wnt signaling pathway, which is involved in regulating early neural development [81]. The 5′-tiRNA Val can directly bind to FZD3 and inhibit FZD3-mediated Wnt/β-catenin pathway [18], which is related to tamoxifen and doxorubicin resistance [82,83]. In addition, the downregulation of FZD3 significantly reduces the expression of cyclin D1 and c-myc [18].…”