Exploring the role of Nrf2 signaling in glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is one of the most aggressive glial cell tumors in adults. Although current treatment options for GBM offer some therapeutic benefit, median survival remains poor and does not generally exceed 14 months. Several genes, such as isocitrate dehydrogenase (IDH) enzyme and O6-methylguanine-DNA methyltransferase (MGMT), have been implicated in pathogenesis of the disease. Treatment is often adapted based on the presence of IDH mutations and MGMT promoter methylation status. Recent GBM cell line studies have associated Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) expression with high-grade tumors. Increased Nrf2 expression is often found in tumors with IDH-1 mutations. Nrf2 is an important transcription factor with anti-apoptotic, antioxidative, anti-inflammatory, and proliferative properties due to its complex interactions with multiple regulatory pathways. In addition, evidence suggests that Nrf2 promotes GBM cell survival in hypoxic environment,by up-regulating hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Downregulation of Nrf2 has been shown to improve GBM sensitivity to chemotherapy drugs such as Temozolomide. Thus, Nrf2 could be a key regulator of GBM pathways and potential therapeutic target. Further research efforts exploring an interplay between Nrf2 and major molecular signaling mechanisms could offer novel GBM drug candidates with a potential to significantly improve patients prognosis.

Combining Pr3+-Doped Nanoradiosensitizers and Endogenous Protoporphyrin IX for X-ray-Mediated Photodynamic Therapy of Glioblastoma Cells

“…The transcription factors Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and tumor protein p53 (p53) control inflammatory and stress responses, thereby supporting GBM survival; they are also linked to the UPR (Figure S13A). Nrf2 protects against oxidative stress, promotes anti-apoptotic and anti-inflammatory responses, and stimulates cell proliferation . High-grade GBM cells often contain elevated levels of Nrf2.…”

“…Nrf2 protects against oxidative stress, promotes anti-apoptotic and anti-inflammatory responses, and stimulates cell proliferation. 59 High-grade GBM cells often contain elevated levels of Nrf2. This improves GBM survival and is linked to poorer treatment outcomes.…”

“…Further relevant to therapeutic intervention, Nrf2 downregulation increases the chemosensitivity of GBM. 59 In our study, Nrf2 abundance was markedly reduced for all conditions that included RLNPs (Figure S13C). Ultimately, these RLNP-dependent changes will diminish the survival of GBM cells, especially under the harsh conditions of the tumor microenvironment.…”

Temozolomide Resistance in Glioblastoma by NRF2: Protecting the Evil

“…However, it is important to note that there is no difference in the mechanism in which NRF2 promotes cell protection, and that the only difference is in the scenario in which the cell is protected: for normal cells, NRF2 activation occurs in a controlled and transient manner, whereas for tumor cells, NRF2 is constitutively activated, conferring cytoprotection and leading to chemotherapy resistance [ 42 ]. Therefore, since NRF2 is a key molecular player involved in many fundamental cellular responses to chemotherapy, it has been explored over the past years as a promising therapeutic pathway in glioblastoma [ 43 ]. In this sense, a recent study from our group, utilizing CRISPR library screening, identified NRF2 as one of the main targets in the context of TMZ resistance, further emphasizing the importance of this pathway in glioblastoma [ 44 ].…”

Senataxin and R-loops homeostasis: multifaced implications in carcinogenesis

“…Intriguingly, KEAP1-USP11 defective tumor cells exhibit BRCAness phenotype, i.e., alteration of R-loops homeostasis, DNA damage, and higher sensitivity to PARP inhibitors [ 116 , 117 ]. Therefore, SETX might represent a therapeutically actionable target to modulate the cytotoxic response of those tumor types carrying aberrant USP11-KEAP1-NRF2 pathway [ 118 – 120 ]. Therefore, a deeper comprehension of the circuits controlling SETX expression might be relevant to unveil novel therapeutically actionable routes in neurological disorders as well as human cancers.…”