PloS one, 2013-01, Vol.8 (1), p.e54193
2013
Details
- Autor(en) / Beteiligte
- Titel
- Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature
- Ist Teil von
- PloS one, 2013-01, Vol.8 (1), p.e54193
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin. An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed. Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines. Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0054193Titel-ID: cdi_plos_journals_1327267275
- Format
- –
- Schlagworte
- AC133 Antigen, Aldehyde Dehydrogenase - metabolism, Analysis, Antigens, CD - metabolism, Antineoplastic Agents - pharmacology, Apoptosis, beta Catenin - metabolism, Biology, Biomarkers, Tumor - metabolism, Biotechnology, Cancer, Cancer therapies, Carcinoma, Non-Small-Cell Lung - metabolism, Carcinoma, Non-Small-Cell Lung - pathology, CD44 antigen, Cell cycle, Cell Cycle - drug effects, Cell death, Cell Line, Tumor, Cell proliferation, Cell Proliferation - drug effects, Cell survival, Cell Survival - drug effects, Cisplatin, Cisplatin - pharmacology, Damage assessment, Dehydrogenases, Deoxyribonucleic acid, DNA, DNA adducts, DNA Adducts - drug effects, DNA damage, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm - drug effects, Flow Cytometry, G1 phase, Glycoproteins - metabolism, Health sciences, Homeodomain Proteins - metabolism, Hospitals, Humans, Hyaluronan Receptors - metabolism, Lung cancer, Lung cancer, Non-small cell, Lung cancer, Small cell, Lung diseases, Lung Neoplasms - metabolism, Lung Neoplasms - pathology, Markers, Medical research, Medicine, Molecular modelling, Nanog Homeobox Protein, Neoplastic Stem Cells - metabolism, Non-small cell lung cancer, Non-small cell lung carcinoma, Oct-4 protein, Octamer Transcription Factor-3 - metabolism, Oncology, Peptides - metabolism, Platinum, Pluripotency, Proteins, Proto-Oncogene Proteins c-met - metabolism, Sensitivity enhancement, Signal transduction, Small cell lung cancer, SOXB1 Transcription Factors - metabolism, Stem cells, Subpopulations, Survival, Tumor cell lines, Tumors, β-Catenin