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ToolsLawani-Luwaji, Ebidor U., Pike, Claire V. S. and Coussons, Peter J. (2025) Retinoic acid-Induced transglutaminase 2 expression reduces sensitivity to cisplatin in the hormone-positive MCF-7 breast cancer cell model. International Journal of Molecular Sciences, 26 (16). ISSN 1661-6596
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Abstract
Cisplatin is an effective chemotherapeutic drug, but is limited both by its toxicity and its tendency to induce drug resistance rapidly in some patients. Tissue transglutaminase 2 (TG2), which is overexpressed in various cancers, has two main isoforms: a long (TG2-L) and a short form (TG2-S). While TG2-L supports cell survival, conversely, TG2-S promotes cell death. Evidence increasingly suggests that TG2 may be a suitable target for combating chemoresistance in a variety of human cancers. Here, we show that cisplatin toxicity towards wild-type MCF-7 breast cancer cells is associated with reduced TG2-L and TG2-S expression, whereas approximately doubling the TG2-L expression through the retinoic acid pre-treatment of these cells induces survival in the presence of cisplatin at levels similar to those seen in long-term cisplatin-co-cultured cells, which have reduced sensitivity. The treatment of cisplatin-surviving cells with cisplatin alone did not significantly alter the levels of either TG2 isoform, whereas the cisplatin challenge of cisplatin-surviving MCF-7 cells following 20 µM retinoic acid pre-treatment resulted in increased levels of TG2-L, increased TG2 enzyme activity, and no significant change in TG2-S levels, with increased cell survival. These findings suggest a subtype-specific regulatory effect of RA in cisplatin-surviving MCF-7 cells, with TG2-L upregulated at higher RA concentrations, potentially contributing to altered cisplatin sensitivity. Anti-TG2 siRNA silencing reduced cisplatin IC50 to base levels in both wild-type and cisplatin-surviving MCF-7 cells, supporting the notion that the modulation of TG2 expression could offer a significant benefit to cisplatin efficacy. Preventing excessive retinoic acid exposure may also be a mechanism for maximising cisplatin efficacy, considering TG2 modulation.
| Item Type: | Article |
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| Additional Information: | Data Availability Statement: The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries, including the raw data supporting the conclusions of this article, can be made to the corresponding author. |
| Uncontrolled Keywords: | breast cancer,cisplatin,dietary retinoids,mcf-7,transglutaminase 2,catalysis,molecular biology,computer science applications,spectroscopy,physical and theoretical chemistry,organic chemistry,inorganic chemistry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1500/1503 |
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| Depositing User: | LivePure Connector |
| Date Deposited: | 06 Oct 2025 09:30 |
| Last Modified: | 11 Oct 2025 15:34 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/100628 |
| DOI: | 10.3390/ijms26168101 |
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