Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin
Despite advances in personalised medicine and the emerging role of immune checkpoints in directing treatment decisions in subsets of lung cancer patients, non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related deaths worldwide. The development of drug resistance plays a k...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-04-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523321000176 |
| _version_ | 1818428778611736576 |
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| author | Lauren MacDonagh Rhyla Mae Santiago Steven G. Gray Eamon Breen Sinead Cuffe Stephen P. Finn Kenneth J. O'Byrne Martin P. Barr |
| author_facet | Lauren MacDonagh Rhyla Mae Santiago Steven G. Gray Eamon Breen Sinead Cuffe Stephen P. Finn Kenneth J. O'Byrne Martin P. Barr |
| author_sort | Lauren MacDonagh |
| collection | DOAJ |
| description | Despite advances in personalised medicine and the emerging role of immune checkpoints in directing treatment decisions in subsets of lung cancer patients, non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related deaths worldwide. The development of drug resistance plays a key role in the relapse of lung cancer patients in the clinical setting, mainly due to the unlimited renewal capacity of residual cancer stem cells (CSCs) within the tumour cell population during chemotherapy. In this study, we investigated the function of the CSC marker, aldehyde dehydrogenase (ALDH1) in retinoic acid cell signalling using an in vitro model of cisplatin resistant NSCLC. The addition of key components in retinoic acid cell signalling, all-trans retinoic acid (ATRA) and retinol to cisplatin chemotherapy, significantly reduced ALDH1-positive cell subsets in cisplatin resistant NSCLC cells relative to their sensitive counterparts resulting in the re-sensitisation of chemo-resistant cells to the cytotoxic effects of cisplatin. Furthermore, combination of ATRA or retinol with cisplatin significantly inhibited cell proliferation, colony formation and increased cisplatin-induced apoptosis. This increase in apoptosis may, at least in part, be due to differential gene expression of the retinoic acid (RARα/β) and retinoid X (RXRα) nuclear receptors in cisplatin-resistant lung cancer cells. These data support the concept of exploiting the retinoic acid signalling cascade as a novel strategy in targeting subsets of CSCs in cisplatin resistant lung tumours. |
| first_indexed | 2024-12-14T15:07:02Z |
| format | Article |
| id | doaj.art-d6db2e7a64e74a76a7ad8670b42262fb |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-14T15:07:02Z |
| publishDate | 2021-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-d6db2e7a64e74a76a7ad8670b42262fb2022-12-21T22:56:41ZengElsevierTranslational Oncology1936-52332021-04-01144101025Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatinLauren MacDonagh0Rhyla Mae Santiago1Steven G. Gray2Eamon Breen3Sinead Cuffe4Stephen P. Finn5Kenneth J. O'Byrne6Martin P. Barr7Thoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, IrelandThoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, IrelandThoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, IrelandFlow Cytometry Facility, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, IrelandThoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland; Medical Oncology Department, St James's Hospital, Dublin, IrelandThoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland; Histopathology Department, St James's Hospital & Trinity College Dublin, IrelandCancer & Ageing Research Program, Queensland University of Technology, Brisbane, AustraliaThoracic Oncology Research Group, School of Clinical Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland; Corresponding author at: Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St James's Hospital & Trinity College Dublin, Ireland.Despite advances in personalised medicine and the emerging role of immune checkpoints in directing treatment decisions in subsets of lung cancer patients, non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related deaths worldwide. The development of drug resistance plays a key role in the relapse of lung cancer patients in the clinical setting, mainly due to the unlimited renewal capacity of residual cancer stem cells (CSCs) within the tumour cell population during chemotherapy. In this study, we investigated the function of the CSC marker, aldehyde dehydrogenase (ALDH1) in retinoic acid cell signalling using an in vitro model of cisplatin resistant NSCLC. The addition of key components in retinoic acid cell signalling, all-trans retinoic acid (ATRA) and retinol to cisplatin chemotherapy, significantly reduced ALDH1-positive cell subsets in cisplatin resistant NSCLC cells relative to their sensitive counterparts resulting in the re-sensitisation of chemo-resistant cells to the cytotoxic effects of cisplatin. Furthermore, combination of ATRA or retinol with cisplatin significantly inhibited cell proliferation, colony formation and increased cisplatin-induced apoptosis. This increase in apoptosis may, at least in part, be due to differential gene expression of the retinoic acid (RARα/β) and retinoid X (RXRα) nuclear receptors in cisplatin-resistant lung cancer cells. These data support the concept of exploiting the retinoic acid signalling cascade as a novel strategy in targeting subsets of CSCs in cisplatin resistant lung tumours.http://www.sciencedirect.com/science/article/pii/S1936523321000176Retinoic acidResistanceCisplatinAldehyde dehydrogenaseCancer stem cells |
| spellingShingle | Lauren MacDonagh Rhyla Mae Santiago Steven G. Gray Eamon Breen Sinead Cuffe Stephen P. Finn Kenneth J. O'Byrne Martin P. Barr Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin Translational Oncology Retinoic acid Resistance Cisplatin Aldehyde dehydrogenase Cancer stem cells |
| title | Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin |
| title_full | Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin |
| title_fullStr | Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin |
| title_full_unstemmed | Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin |
| title_short | Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin |
| title_sort | exploitation of the vitamin a retinoic acid axis depletes aldh1 positive cancer stem cells and re sensitises resistant non small cell lung cancer cells to cisplatin |
| topic | Retinoic acid Resistance Cisplatin Aldehyde dehydrogenase Cancer stem cells |
| url | http://www.sciencedirect.com/science/article/pii/S1936523321000176 |
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