A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells
Purpose Glioblastoma Multiforme (GBM) is the commonest brain tumour in adults. A population of cells, known as cancer stem cells (CSCs), is thought to mediate chemo/radiotherapy resistance. CD133 is a cell surface marker to identify and isolate CSCs. However, its functional significance and the...
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| Format: | Article |
| Published: |
Springer
2018
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| Online Access: | https://eprints.nottingham.ac.uk/49861/ |
| _version_ | 1848798096047210496 |
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| author | Ahmed, Eroje M. Bandopadhyay, Gagori Coyle, Beth Grabowska, Anna M. |
| author_facet | Ahmed, Eroje M. Bandopadhyay, Gagori Coyle, Beth Grabowska, Anna M. |
| author_sort | Ahmed, Eroje M. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Purpose
Glioblastoma Multiforme (GBM) is the commonest brain tumour in adults. A population of cells, known as cancer stem cells (CSCs), is thought to mediate chemo/radiotherapy resistance. CD133 is a cell surface marker to identify and isolate CSCs. However, its functional significance and the relevant microenvironment in which to study CD133 remain unknown. We examined the influence of hypoxia on CD133 expression and the potential functional significance of CD133 in glioblastoma chemoresistance.
Methods
Gene expression was analysed by qRT-PCR. siRNA technique was used to downregulate genes and confirmed by flow cytometry. IC50 values was evaluated with the Alamar blue assay.
Results
CD133 expression was upregulated in hypoxia in 2D and 3D models. There was increased resistance to chemotherapeutics, cisplatin, temozolomide and etoposide, in cells cultured in hypoxia compared to normoxia. siRNA knockdown of either HIF1a or HIF2a resulted in reduced CD133 mRNA expression with HIF2a having a more prolonged effect on CD133 expression. HIF2a downregulation sensitized GBM cells to cisplatin to a greater extent than HIF1a but CD133 knockdown had a much more marked effect on cisplatin sensitisation than knockdown of either of the HIFs suggesting a HIF-independent mechanism of cisplatin resistance mediated via CD133. The same mechanism was not involved in temozolomide resistance since downregulation of HIF1a but not HIF2a or CD133 sensitized GBM cells to temozolomide.
Conclusion
Knowledge of the mechanisms involved in the novel hypoxia-induced CD133-mediated resistance to cisplatin observed might lead to identification of new strategies that enable more effective use of current therapeutic agents. |
| first_indexed | 2025-11-14T20:14:20Z |
| format | Article |
| id | nottingham-49861 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:14:20Z |
| publishDate | 2018 |
| publisher | Springer |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-498612020-05-04T19:43:42Z https://eprints.nottingham.ac.uk/49861/ A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells Ahmed, Eroje M. Bandopadhyay, Gagori Coyle, Beth Grabowska, Anna M. Purpose Glioblastoma Multiforme (GBM) is the commonest brain tumour in adults. A population of cells, known as cancer stem cells (CSCs), is thought to mediate chemo/radiotherapy resistance. CD133 is a cell surface marker to identify and isolate CSCs. However, its functional significance and the relevant microenvironment in which to study CD133 remain unknown. We examined the influence of hypoxia on CD133 expression and the potential functional significance of CD133 in glioblastoma chemoresistance. Methods Gene expression was analysed by qRT-PCR. siRNA technique was used to downregulate genes and confirmed by flow cytometry. IC50 values was evaluated with the Alamar blue assay. Results CD133 expression was upregulated in hypoxia in 2D and 3D models. There was increased resistance to chemotherapeutics, cisplatin, temozolomide and etoposide, in cells cultured in hypoxia compared to normoxia. siRNA knockdown of either HIF1a or HIF2a resulted in reduced CD133 mRNA expression with HIF2a having a more prolonged effect on CD133 expression. HIF2a downregulation sensitized GBM cells to cisplatin to a greater extent than HIF1a but CD133 knockdown had a much more marked effect on cisplatin sensitisation than knockdown of either of the HIFs suggesting a HIF-independent mechanism of cisplatin resistance mediated via CD133. The same mechanism was not involved in temozolomide resistance since downregulation of HIF1a but not HIF2a or CD133 sensitized GBM cells to temozolomide. Conclusion Knowledge of the mechanisms involved in the novel hypoxia-induced CD133-mediated resistance to cisplatin observed might lead to identification of new strategies that enable more effective use of current therapeutic agents. Springer 2018-06-30 Article PeerReviewed Ahmed, Eroje M., Bandopadhyay, Gagori, Coyle, Beth and Grabowska, Anna M. (2018) A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells. Cellular Oncology, 41 (3). pp. 319-328. ISSN 2211-3436 Hypoxia; Cisplatin; Temozolomide; Chemoresistance; CD133; HIFs https://link.springer.com/article/10.1007/s13402-018-0374-8 doi:10.1007/s13402-018-0374-8 doi:10.1007/s13402-018-0374-8 |
| spellingShingle | Hypoxia; Cisplatin; Temozolomide; Chemoresistance; CD133; HIFs Ahmed, Eroje M. Bandopadhyay, Gagori Coyle, Beth Grabowska, Anna M. A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells |
| title | A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells |
| title_full | A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells |
| title_fullStr | A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells |
| title_full_unstemmed | A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells |
| title_short | A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells |
| title_sort | hif-independent, cd133-mediated mechanism of cisplatin resistance in glioblastoma cells |
| topic | Hypoxia; Cisplatin; Temozolomide; Chemoresistance; CD133; HIFs |
| url | https://eprints.nottingham.ac.uk/49861/ https://eprints.nottingham.ac.uk/49861/ https://eprints.nottingham.ac.uk/49861/ |