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
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 function...
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doaj-51fdd163b27e4e0490daff94c804fa152020-11-24T21:22:11ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-07-012015369610.3390/ijms20153696ijms20153696Downregulation 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 DoxorubicinWalhan Alshaer0Dana A. Alqudah1Suha Wehaibi2Duaa Abuarqoub3Malek Zihlif4Ma’mon M. Hatmal5Abdalla Awidi6Cell Therapy Center, The University of Jordan, Amman 11942, JordanCell Therapy Center, The University of Jordan, Amman 11942, JordanCell Therapy Center, The University of Jordan, Amman 11942, JordanCell Therapy Center, The University of Jordan, Amman 11942, JordanDepartment of Pharmacology, Faculty of Medicine, The University of Jordan, Amman 11942, JordanDepartment of Medical Laboratory Sciences, Faculty of Applied Health Sciences, Hashemite University, Zarqa 13133, JordanCell Therapy Center, The University of Jordan, Amman 11942, JordanCombinatorial 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<sup>−</sup>/CD24<sup>+</sup> 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.https://www.mdpi.com/1422-0067/20/15/3696breast cancersiRNANotch-1STAT3β-catenindoxorubicindrug-resistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Walhan Alshaer Dana A. Alqudah Suha Wehaibi Duaa Abuarqoub Malek Zihlif Ma’mon M. Hatmal Abdalla Awidi |
spellingShingle |
Walhan Alshaer Dana A. Alqudah Suha Wehaibi Duaa Abuarqoub Malek Zihlif Ma’mon M. Hatmal Abdalla Awidi 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 International Journal of Molecular Sciences breast cancer siRNA Notch-1 STAT3 β-catenin doxorubicin drug-resistance |
author_facet |
Walhan Alshaer Dana A. Alqudah Suha Wehaibi Duaa Abuarqoub Malek Zihlif Ma’mon M. Hatmal Abdalla Awidi |
author_sort |
Walhan Alshaer |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-07-01 |
description |
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<sup>−</sup>/CD24<sup>+</sup> 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. |
topic |
breast cancer siRNA Notch-1 STAT3 β-catenin doxorubicin drug-resistance |
url |
https://www.mdpi.com/1422-0067/20/15/3696 |
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