Radio resistance in breast cancer cells is mediated through TGF-β signalling, hybrid epithelial-mesenchymal phenotype and cancer stem cells
| Autor: | Poonam Yadav, Bhavani S. Shankar |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Homeobox protein NANOG Epithelial-Mesenchymal Transition HMGA2 Cell Survival Hybrid E/M phenotype Breast Neoplasms RM1-950 Radiation Dosage Radiation Tolerance Radio-resistance 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine SOX2 Transforming Growth Factor beta Cancer stem cell Humans Propidium iodide Clonogenic assay Pharmacology Zeb-1 biology CD44 General Medicine TGF-β isoforms Phenotype 030104 developmental biology Snail chemistry Apoptosis Cell culture 030220 oncology & carcinogenesis MCF-7 Cells Neoplastic Stem Cells Cancer research biology.protein Female Therapeutics. Pharmacology Signal Transduction |
| Zdroj: | Biomedicine & Pharmacotherapy, Vol 111, Iss, Pp 119-130 (2019) |
| ISSN: | 0753-3322 |
| DOI: | 10.1016/j.biopha.2018.12.055 |
| Popis: | Aims A major obstacle for effective cancer treatment by radiation therapy is the development of radio-resistance and identification of underlying mechanisms and activated pathways will lead to better combination therapies. Main methods Irradiated MCF-7 and MDA-MB-231 breast cancer cell lines were characterised following different recovery periods. Proliferation was assessed by MTT, BrdU and clonogenic assays and apoptosis by Annexin V/ propidium iodide staining and flow cytometry. Gene expression was monitored by real time PCR/ELISA/antibody labelling and migration using transwell inserts. Key findings Breast cancer cell lines exposed to 6 Gy followed by recovery period for 7 days (D7-6 G) had increased ability for proliferation as well as apoptosis. D7-6 G from both cell lines had increased expression of transforming growth factor isoforms (TGF)-β1, β2 and β3, their receptors TGF-βR1 and TGF-βR2 which are known for such dual effects. The expression of downstream transcription factors Snail, Zeb-1 and HMGA2 also showed a differential pattern in D7-6 G cells with upregulation of at least two of these transcription factors. D7-6 G cells from both cell lines displayed hybrid epithelial-mesenchymal (E/M) phenotype with increased expression of E/M markers and migration. D7-6 G cells had increased expression of cancer stem cells markers Oct4, Sox2, and Nanog; aldehyde dehydrogenase expression and activity; proportion of CD44+CD24−cells. This was accompanied by radio resistance when exposed to a challenge dose of radiation. Treatment with TGF-βRI inhibitor abrogated the increase in proliferation of D7-6 G cells. Significance Blocking of TGF-β signalling may therefore be an effective strategy for overcoming radio resistance induced by radiation exposure. |
| Databáze: | OpenAIRE |
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