| dc.contributor.author | O'BYRNE, KEN | en |
| dc.date.accessioned | 2014-12-11T10:41:12Z | |
| dc.date.available | 2014-12-11T10:41:12Z | |
| dc.date.issued | 2013 | en |
| dc.date.submitted | 2013 | en |
| dc.identifier.citation | Barr, MP, Gray, SG, Hoffmann, AC, Hilger, RA, Thomale, J, O'Flaherty, JD, Fennell, DA, Richard, D, O'Leary, JJ, O'Byrne, KJ, Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature, PLOS ONE, 8, 1, 2013, 54193- | en |
| dc.identifier.other | Y | en |
| dc.description | PUBLISHED | en |
| dc.description.abstract | NTRODUCTION:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSION:
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 | en |
| dc.description.sponsorship | markers support the presence of a chemoresistant population of
lung cancer cells with a stem-like signature that may be useful as
a clinically relevant
in vitro
model for studying mechanisms of
cisplatin resistance in NSCLC. Moreover, we have identified
differences in cisplatin-DNA adduct formation and DNA repair of
cisplatin-induced DSB’s between parent and chemoresistant cells
following uptake of cisplatin. These findings provide a rationale for
more specific therapeutic targeting in the treatment of this disease.
Acknowledgments
Thanks to Dr Michael F. Gallagher, Department of Histopathology,
Trinity College Dublin, for reading this manuscript.
Author Contributions
Provision of support and advice on cisplatin resistance: DR DF JJO.
Reading of the Manuscript: JDO. Conceived and designed the
experiments: MPB KJO. Performed the experiments: MPB. Analyzed
the data: MPB ACH JT RAH JJO. Contributed reagents/materials/
analysis tools: MPB SGG DF DR. Wrote the paper: MPB. | en |
| dc.format.extent | 54193 | en |
| dc.language.iso | en | en |
| dc.relation.ispartofseries | PLOS ONE | en |
| dc.relation.ispartofseries | 8 | en |
| dc.relation.ispartofseries | 1 | en |
| dc.rights | Y | en |
| dc.subject | NSCLC cells | en |
| dc.subject.lcsh | NSCLC cells | en |
| dc.title | Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature | en |
| dc.type | Journal Article | en |
| dc.type.supercollection | scholarly_publications | en |
| dc.type.supercollection | refereed_publications | en |
| dc.identifier.peoplefinderurl | http://people.tcd.ie/obyrneke | en |
| dc.identifier.rssinternalid | 96308 | en |
| dc.identifier.doi | http://dx.doi.org/10.1371/journal.pone.0054193 | en |
| dc.rights.ecaccessrights | openAccess | |
| dc.subject.TCDTheme | Cancer | en |
| dc.identifier.uri | http://hdl.handle.net/2262/72409 | |
