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. 2021 Apr;14(4):101025.
doi: 10.1016/j.tranon.2021.101025. Epub 2021 Feb 5.

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

Lauren MacDonagh  1 , Rhyla Mae Santiago  2 , Steven G Gray  3 , Eamon Breen  4 , Sinead Cuffe  5 , Stephen P Finn  6 , Kenneth J O'Byrne  7 , Martin P Barr  8
Affiliations

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

Lauren MacDonagh et al. Transl Oncol. 2021 Apr.

Abstract

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.

Keywords: Aldehyde dehydrogenase; Cancer stem cells; Cisplatin; Resistance; Retinoic acid.

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Conflict of interest statement

Declaration of Competing Interest The authors have no conflicts of interests to declare.

Figures

Fig 1
Fig. 1
Cisplatin resistant NSCLC cells exhibit increased proliferation and ALDH1 activity.
Fig 2
Fig. 2
Products and substrates of the retinoic acid pathway inhibit ALDH1-positive CSC populations in cisplatin resistant cells.
Fig 3
Fig. 3
ATRA and retinol enhance the cytotoxic effects of cisplatin.
Fig 4
Fig. 4
Clonogenic survival is significantly altered in cisplatin resistant lung cancer cells in response to supplementation of vitamin A/retinoic acid pathway components.
Fig 5
Fig. 5
Cisplatin-induced apoptosis of chemo-resistant NSCLC cells is enhanced in response to ATRA and retinol.
Fig 6
Fig. 6
Expression of the retinoic acid and retinoid X receptors in NSCLC cells is altered in response to ATRA.
Fig 7
Fig. 7
Gene expression profile of stemness markers is altered in cisplatin resistant ALDH1-positive cell fractions.
See this image and copyright information in PMC

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