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Cited by 38Melanoma and MAPK PathwaysCancer Cells and MetastasisTGF-β signaling in diseases

Phenotype characterization of human melanoma cells resistant to dabrafenib

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Cordaro, Fabiola Gilda, De Presbiteris, Anna Lisa, Camerlingo, Rosa, Mozzillo, Nicola, Pirozzi, Giuseppe, Cavalcanti, Ernesta, Manca, Antonella, Palmieri, Giuseppe +6 more·2017·Oncology Reports
DOI 10.3892/or.2017.5963PMC PMC5780027
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Abstract

In the present study, the phenotype of melanoma cells resistant to dabrafenib (a B-RAF inhibitor) was investigated, to shed more light on melanoma resistance to B-RAF inhibition. Melanoma cells resistant to dabrafenib were generated using 3 different cell lines, A375, 397 and 624.38, all carrying B-RAFV600E, and they were characterized by cytofluorometric analysis, Ion Torrent technology, immunofluorescence and biochemistry. All dabrafenib-resistant cells showed, in addition to a re-activation of MAPK signaling, morphological changes compared to their sensitive counterparts, accompanied by an increase in CD90 (mesenchymal marker) expression and a decrease in E-cadherin (epithelial marker) expression, suggesting an epithelial-to-mesenchymal-like phenotypic transition. However, melanoma cells with TGF-β1-induced epithelial-to-mesenchymal transition (EMT) were more sensitive to dabrafenib treatment compared to the sensitivity noted in the non-TGF‑β1‑induced EMT melanoma cells, suggesting that TGF-β1-induced EMT was not associated with dabrafenib resistance. Although dabrafenib-resistant cells exhibited increased cell motility and E-cadherin/vimentin reorganization, as expected in EMT, all of them showed unvaried E-cadherin mRNA and unchanged Snail protein levels, while Twist1 protein expression was decreased with the exception of A375 dabrafenib-resistant melanoma cells, where it was unaffected. These findings suggest a distinct active EMT-like process adopted by melanoma cells under drug exposure. Furthermore, dabrafenib-resistant cells exhibited stem cell-like features, with Oct4 translocation from the cytoplasm to peri-nuclear sites and nuclei, and increased CD20 expression. In conclusion, our data, in addition to confirming that resistance to dabrafenib is dependent on re-activation of MAPK signaling, suggest that this resistance is linked to a distinct active EMT-like process as well as stem-cell features adopted by melanoma cells.

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Authors
Cordaro, F. G., De Presbiteris, A. L., Camerlingo, R., Mozzillo, N., Pirozzi, G., Cavalcanti, E., Manca, A., Palmieri, G., Cossu, A., Ciliberto, G., Ascierto, P. A., Travali, S., Patriarca, E. J., & Caputo, E.
Affiliations
  • Institute of Genetics and Biophysics (IT)
  • Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
  • Istituto di Chimica Biomolecolare (IT)
  • Azienda Ospedaliero Universitaria di Sassari (IT)
  • University of Catania (IT)
Corresponding author
Caputo, Emilia
ORCID
Venue
Oncology Reports
Publisher
Spandidos Publications
Published
2017-09-18
Volume
38
Issue
5
Pages
2741-2751
ISSN
  • 1021-335X (ISSN-L)
  • 1791-2431
DOI
10.3892/or.2017.5963
PMC
PMC5780027
OpenAlex
W2756272041
Cited by
38
References
1
Citations by year
2026: 3 · 2025: 4 · 2024: 8 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 6 · 2019: 8 · 2017: 2
FWCI
1.79
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Oncology Reports (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UnissResearch (Università degli Studi di Sassari) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
melanoma, BRAF V600E mutation, epithelial-mesenchymal transition, TGF-β1, E-cadherin, CD90, TWIST1, Oct4, CD20, cell motility, drug resistance
MeSH terms
Humans, Imidazoles, Melanoma, Mutation, Oximes, Phenotype, Biomarkers, Tumor, Vimentin, Antigens, CD, Cadherins, Thy-1 Antigens, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Octamer Transcription Factor-3, Epithelial-Mesenchymal Transition

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