Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11
Drayton RM, Dudziec E, Peter S, Bertz S, Hartmann A, Bryant HE, Catto JWF (2014)
Publication Type: Journal article
Publication year: 2014
Journal
Publisher: American Association for Cancer Research
Book Volume: 20
Pages Range: 1990-2000
Journal Issue: 7
DOI: 10.1158/1078-0432.CCR-13-2805
Abstract
Resistance to cisplatin-based chemotherapy is a major obstacle to bladder cancer treatment. We aimed to identify microRNAs (miRNA) that are dysregulated in cisplatin-resistant disease, ascertain how these contribute to a drug-resistant phenotype, and how this resistance might be overcome.miRNA expression in paired cisplatin-resistant and -sensitive cell lines was measured. Dysregulated miRNAs were further studied for their ability to mediate resistance. The nature of the cisplatin-resistant phenotype was established by measurement of cisplatin/DNA adducts and intracellular glutathione (GSH). Candidate miRNAs were examined for their ability to (i) mediate resistance and (ii) alter the expression of a candidate target protein (SLC7A11); direct regulation of SLC7A11 was confirmed using a luciferase assay. SLC7A11 protein and mRNA, and miRNA-27a were quantified in patient tumor material.A panel of miRNAs were found to be dysregulated in cisplatin-resistant cells. miRNA-27a was found to target the cystine/glutamate exchanger SLC7A11 and to contribute to cisplatin resistance through modulation of GSH biosynthesis. In patients, SLC7A11 expression was inversely related to miRNA-27a expression, and those tumors with high mRNA expression or high membrane staining for SLC7A11 experienced poorer clinical outcomes. Resistant cell lines were resensitized by restoring miRNA-27a expression or reducing SLC7A11 activity with siRNA or with sulfasalazine.Our findings indicate that miRNA-27a negatively regulates SLC7A11 in cisplatin-resistant bladder cancer, and shows promise as a marker for patients likely to benefit from cisplatin-based chemotherapy. SLC7A11 inhibition with sulfasalazine may be a promising therapeutic approach to the treatment of cisplatin-resistant disease.
Authors with CRIS profile
Simone Bertz
Institute of Pathology
Arndt Hartmann
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Involved external institutions
United Kingdom (GB)How to cite
APA:
Drayton, R.M., Dudziec, E., Peter, S., Bertz, S., Hartmann, A., Bryant, H.E., & Catto, J.W.F. (2014). Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11. Clinical Cancer Research, 20(7), 1990-2000. https://doi.org/10.1158/1078-0432.CCR-13-2805
MLA:
Drayton, Ross M., et al. "Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11." Clinical Cancer Research 20.7 (2014): 1990-2000.
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