Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization
Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but u...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/10/12/495 |
| _version_ | 1797757811439960064 |
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| author | Bastian Jakubzig Fabian Baltes Svenja Henze Martin Schlesinger Gerd Bendas |
| author_facet | Bastian Jakubzig Fabian Baltes Svenja Henze Martin Schlesinger Gerd Bendas |
| author_sort | Bastian Jakubzig |
| collection | DOAJ |
| description | Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes. |
| first_indexed | 2024-03-12T18:20:53Z |
| format | Article |
| id | doaj.art-203f13a2b41344bb946e185d0c4ab746 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T18:20:53Z |
| publishDate | 2018-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-203f13a2b41344bb946e185d0c4ab7462023-08-02T08:51:59ZengMDPI AGCancers2072-66942018-12-01101249510.3390/cancers10120495cancers10120495Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell SensitizationBastian Jakubzig0Fabian Baltes1Svenja Henze2Martin Schlesinger3Gerd Bendas4Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53123 Bonn, GermanyPharmaceutical Institute, University of Bonn, An der Immenburg 4, 53123 Bonn, GermanyPharmaceutical Institute, University of Bonn, An der Immenburg 4, 53123 Bonn, GermanyPharmaceutical Institute, University of Bonn, An der Immenburg 4, 53123 Bonn, GermanyPharmaceutical Institute, University of Bonn, An der Immenburg 4, 53123 Bonn, GermanyTumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes.https://www.mdpi.com/2072-6694/10/12/495breast cancerCAM-DRCREBcisplatincollagenFAKintegrinMAPKmitoxantroneWnt signaling |
| spellingShingle | Bastian Jakubzig Fabian Baltes Svenja Henze Martin Schlesinger Gerd Bendas Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization Cancers breast cancer CAM-DR CREB cisplatin collagen FAK integrin MAPK mitoxantrone Wnt signaling |
| title | Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization |
| title_full | Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization |
| title_fullStr | Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization |
| title_full_unstemmed | Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization |
| title_short | Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization |
| title_sort | mechanisms of matrix induced chemoresistance of breast cancer cells deciphering novel potential targets for a cell sensitization |
| topic | breast cancer CAM-DR CREB cisplatin collagen FAK integrin MAPK mitoxantrone Wnt signaling |
| url | https://www.mdpi.com/2072-6694/10/12/495 |
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