Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells-Deciphering Novel Potential Targets for a Cell Sensitization
| Autor: | Martin Schlesinger, Bastian Jakubzig, Gerd Bendas, Svenja Henze, Fabian Baltes |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway collagen Cancer Research integrin Cell cisplatin lcsh:RC254-282 Article mitoxantrone 03 medical and health sciences 0302 clinical medicine breast cancer CAM-DR medicine Cytotoxic T cell Cell adhesion Protein kinase B PI3K/AKT/mTOR pathway FAK Chemistry CREB Wnt signaling pathway lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens MAPK Wnt signaling 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Signal transduction |
| Zdroj: | Cancers Volume 10 Issue 12 Cancers, Vol 10, Iss 12, p 495 (2018) |
| ISSN: | 2072-6694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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