@article{dc9756563269412587dceb579a726c47,
title = "Proteome analysis of NRF2 inhibition in melanoma reveals CD44 up-regulation and increased apoptosis resistance upon vemurafenib treatment",
abstract = "Malignant melanoma is the deadliest form of skin cancer and NRF2 has been proposed as a main regulator of tumor cell malignancy. Still the mechanisms how NRF2 is contributing to melanoma progression are incompletely understood. Here we analyzed the effects of either NRF2 induction or depletion, and we also quantified changes on the whole cell proteome level. Our results showed that inhibition of NRF2 leads to a loss of reactive oxygen species protection, but at the same time to an induction of an epithelial mesenchymal transition (EMT) phenotype and an up-regulation of the stem cell marker CD44. Additionally, cells devoid of NRF2 showed increased cell viability after treatment with a MYC and a BRAF inhibitor. Importantly, survival upon vemurafenib treatment was dependent on CD44 expression. Finally, analysis of archival melanoma patient samples confirmed a vice versa relationship of NRF2 and CD44 expression. In summary, we recorded changes in the proteome after NRF2 modulation in melanoma cells. Surprisingly, we identified that NRF2 inhibition lead to induction of an EMT phenotype and an increase in survival of cells after apoptosis induction. Therefore, we propose that it is important for future therapies targeting NRF2 to consider blocking EMT promoting pathways in order to achieve efficient tumor therapy.",
keywords = "B Raf kinase, cell marker, Hermes antigen, Myc protein, proteome, reactive oxygen metabolite, transcription factor Nrf2, vemurafenib, CD44 protein, human, hyaluronic acid binding protein, adolescent, adult, aged, antigen expression, apoptosis, Article, cancer cell culture, cell survival, cell viability, clinical article, cohort analysis, epithelial mesenchymal transition, female, human cell, human tissue, immunofluorescence, male, melanoma, protein targeting, proteomics, quantitative analysis, real time polymerase chain reaction, retrospective study, signal transduction, upregulation, genetics, metabolism, tumor cell line, Apoptosis, Cell Line, Tumor, Humans, Hyaluronan Receptors, Melanoma, NF-E2-Related Factor 2, Proteome, Proto-Oncogene Proteins B-raf, Up-Regulation, Vemurafenib, combination therapy, redox homeostasis, anti-oxidant response, malignant melanoma, Hyaluronan Receptors/genetics, Proteome/metabolism, Cell Line, Tumor, NF-E2-Related Factor 2/genetics, Proto-Oncogene Proteins B-raf/genetics, Melanoma/drug therapy, Vemurafenib/pharmacology",
author = "H.P. Weitzenb{\"O}ck and A. Gschwendtner and C. Wiesner and M. Depke and F. Schmidt and F. Trautinger and M. Hengstschl{\"a}ger and H. Hundsberger and M. Mikula",
note = "Funding Information: This research was funded by the Gesellschaft f{\"u}r Forschungsf{\"o}rderung Nieder{\"o}sterreich m.b.H. grant number LS14‐007 and by the Austrian Science Fund (FWF), grant number P 32979. We thank Christian Hentschker for mass spectrometric data acquisition, Leif Steil for help in data processing, and Uwe V{\"o}lker for lab space and instrumentation (Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany). The results for gene expression in patient cohorts are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga . Publisher Copyright: {\textcopyright} 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",
year = "2021",
month = dec,
day = "23",
doi = "10.1002/cam4.4506",
language = "English",
volume = "11",
pages = "956--967",
journal = "Cancer Medicine",
issn = "2045-7634",
publisher = "John Wiley and Sons Ltd",
number = "4",
}
