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

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de Souza, I ; Monteiro, L. K. S. ; Guedes, C. B. ; Silva, M. M. ; Andrade-Tomaz, M. ; Contieri, B. ; Latancia, M. T. ; Mendes, D. ; Porchia, B. F. M. M. ; Lazarini, M. ; Gomes, L. R. ; Rocha, C. R. R.
Total Authors: 12
Document type: Journal article
Source: CELL DEATH & DISEASE; v. 13, n. 7, p. 13-pg., 2022-07-08.
Abstract

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. (AU)

FAPESP's process: 19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg)
Grantee:Carlos Frederico Martins Menck
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 19/26268-6 - Exploring the role of ferroptosis in temozolomide death induction in glioblastoma
Grantee:Izadora de Souza
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 19/15320-7 - Construction of fluorescently-labeled cell lines to evaluate cancer-associated processes in live cells
Grantee:Nadja Cristhina de Souza Pinto
Support Opportunities: Regular Research Grants
FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
Grantee:Hugo Aguirre Armelin
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 19/21745-0 - Exploring drug resistance mechanisms in cancer cells via CRISPR libraries
Grantee:Clarissa Ribeiro Reily Rocha
Support Opportunities: Regular Research Grants
FAPESP's process: 19/27080-0 - Role of chaperone-mediated autophagy in breast cancer
Grantee:Luciana Rodrigues Gomes
Support Opportunities: Regular Research Grants
FAPESP's process: 09/53840-0 - Fluorescence system for investigations of physiological and pathophysiological aspects in cellular models
Grantee:Adriana Karaoglanovic Carmona
Support Opportunities: Multi-user Equipment Program