دورية أكاديمية
أعرض في EDS

High levels of NRF2 sensitize temozolomide-resistant glioblastoma cells to ferroptosis via ABCC1/MRP1 upregulation.

التفاصيل البيبلوغرافية
العنوان: High levels of NRF2 sensitize temozolomide-resistant glioblastoma cells to ferroptosis via ABCC1/MRP1 upregulation.
المؤلفون: de Souza I; Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, 04037-003, Brazil., Monteiro LKS; Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, 04037-003, Brazil., Guedes CB; Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, 04037-003, Brazil., Silva MM; Institute of Biomedical Science, University of São Paulo (USP), São Paulo, 04037-003, Brazil., Andrade-Tomaz M; Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, 04037-003, Brazil., Contieri B; Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, 04037-003, Brazil., Latancia MT; Institute of Biomedical Science, University of São Paulo (USP), São Paulo, 04037-003, Brazil., Mendes D; Institute of Biomedical Science, University of São Paulo (USP), São Paulo, 04037-003, Brazil., Porchia BFMM; Institute of Biomedical Science, University of São Paulo (USP), São Paulo, 04037-003, Brazil., Lazarini M; Department of Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), São Paulo, 04037-003, Brazil., Gomes LR; Cell Cycle Laboratory, Butantan Institute, São Paulo, Brazil., Rocha CRR; Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, 04037-003, Brazil. clarissa.rocha@unifesp.br.
المصدر: Cell death & disease [Cell Death Dis] 2022 Jul 08; Vol. 13 (7), pp. 591. Date of Electronic Publication: 2022 Jul 08.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Pub. Group
مواضيع طبية MeSH: Ferroptosis* , Glioblastoma*/drug therapy , Glioblastoma*/genetics , Glioblastoma*/metabolism , Glioma*/metabolism, NF-E2-Related Factor 2/*metabolism, Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; Humans ; Multidrug Resistance-Associated Proteins ; NF-E2-Related Factor 2/genetics ; Temozolomide/pharmacology ; Temozolomide/therapeutic use ; Up-Regulation
مستخلص: Glioblastoma patients have a poor prognosis mainly due to temozolomide (TMZ) resistance. NRF2 is an important transcript factor involved in chemotherapy resistance due to its protective role in the transcription of genes involved in cellular detoxification and prevention of cell death processes, such as ferroptosis. However, the relation between NRF2 and iron-dependent cell death in glioma is still poorly understood. Therefore, in this study, we analyzed the role of NRF2 in ferroptosis modulation in glioblastoma cells. Two human glioblastoma cell lines (U251MG and T98G) were examined after treatment with TMZ, ferroptosis inducers (Erastin, RSL3), and ferroptosis inhibitor (Ferrostatin-1). Our results demonstrated that T98G was more resistant to chemotherapy compared to U251MG and showed elevated levels of NRF2 expression. Interestingly, T98G revealed higher sensitivity to ferroptosis, and significant GSH depletion upon system xc - blockage. NRF2 silencing in T98G cells (T98G-shNRF2) significantly reduced the viability upon TMZ treatment. On the other hand, T98G-shNRF2 was resistant to ferroptosis and reverted intracellular GSH levels, indicating that NRF2 plays a key role in ferroptosis induction through GSH modulation. Moreover, silencing of ABCC1, a well-known NRF2 target that diminishes GSH levels, has demonstrated a similar collateral sensitivity. T98G-siABCC1 cells were more sensitive to TMZ and resistant to Erastin. Furthermore, we found that NRF2 positively correlates with ABCC1 expression in tumor tissues of glioma patients, which can be associated with tumor aggressiveness, drug resistance, and poor overall survival. Altogether, our data indicate that high levels of NRF2 result in collateral sensitivity on glioblastoma via the expression of its pro-ferroptotic target ABCC1, which contributes to GSH depletion when the system xc - is blocked by Erastin. Thus, ferroptosis induction could be an important therapeutic strategy to reverse drug resistance in gliomas with high NRF2 and ABCC1 expression.
(© 2022. The Author(s).)
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المشرفين على المادة: 0 (Multidrug Resistance-Associated Proteins)
0 (NF-E2-Related Factor 2)
0 (NFE2L2 protein, human)
Y49M64GZ4Q (multidrug resistance-associated protein 1)
YF1K15M17Y (Temozolomide)
تواريخ الأحداث: Date Created: 20220708 Date Completed: 20220712 Latest Revision: 20230119
رمز التحديث: 20230120
مُعرف محوري في PubMed: PMC9270336
DOI: 10.1038/s41419-022-05044-9
PMID: 35803910
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-4889
DOI:10.1038/s41419-022-05044-9