Temozolomide Resistance in Glioblastoma by NRF2: Protecting the Evil

Abstract

The transcription factor NRF2 is constitutively active in glioblastoma, a highly aggressive brain tumor subtype with poor prognosis. Temozolomide (TMZ) is the primary chemotherapeutic agent for this type of tumor treatment, but resistance to this drug is often observed. This review highlights the research that is demonstrating how NRF2 hyperactivation creates an environment that favors the survival of malignant cells and protects against oxidative stress and TMZ. Mechanistically, NRF2 increases drug detoxification, autophagy, DNA repair, and decreases drug accumulation and apoptotic signaling. Our review also presents potential strategies for targeting NRF2 as an adjuvant therapy to overcome TMZ chemoresistance in glioblastoma. Specific molecular pathways, including MAPKs, GSK3β, βTRCP, PI3K, AKT, and GBP, that modulate NRF2 expression leading to TMZ resistance are discussed, along with the importance of identifying NRF2 modulators to reverse TMZ resistance and develop new therapeutic targets. Despite the significant progress in understanding the role of NRF2 in GBM, there are still unanswered questions regarding its regulation and downstream effects. Future research should focus on elucidating the precise mechanisms by which NRF2 mediates resistance to TMZ, and identifying potential novel targets for therapeutic intervention.

Keywords: NRF2; glioblastoma; temozolomide.

Figure 1

Canonical and non-canonical NRF2 pathways. (A) NRF2 proteasomal degradation under constitutive conditions. The ETGE and DLG motifs of NRF2 bind to the KEAP1 Kelch domains; this binding causes the ubiquitin ligase CUL3/RBX1 E2 to join the complex, in which CUL3 acts as a scaffold protein that binds to the BTB domain of KEAP1, allowing the formation of a complex with a ubiquitin-conjugating enzyme (E2). (B) Under oxidative and/or electrophilic stress, KEAP1 undergoes a conformational change, which interrupts the Kelch/DLG binding and leads to its detachment from NRF2, thus the degradation of NRF2 is interrupted and it translocates to the nucleus. (C) Non-canonical pathway of P62-mediated NRF2 activation. When autophagic flux is compromised and P62 accumulates, KEAP1 is sequestered by P62 and does not bind to NRF2, stopping its degradation. Created with BioRender.

Figure 2

NRF2/KEAP1 mutations. (A) The somatic mutations in NRF2 are mostly localized in DLG and ETGE motifs, corresponding to the KEAP1 binding sites. These mutations lead to an increase in NRF2 activity. (B) As for KEAP1, the mutations are found throughout the entire gene, which leads to protein function loss, promoting, as a consequence, high levels of NRF2. All the reported mutations are listed in the COSMIC (Catalogue of Somatic Mutations in Cancer) database. Created with BioRender.

Figure 3

Drug detoxification mediated by NRF2 in cancer cells. The high activation of NRF2 promotes an increase in the GSH synthesis via the induction of GCLM and GCLC. (A) Once GSH is synthesized, the GST induces its binding to the chemotherapeutic drug and the GSH–drug conjugate is exported out of the cell through the multidrug resistance-associated proteins (MRPs) channel. In addition, GPX controls the ROS levels generated by the drug. These mechanisms lead to an increase in resistance to antitumor drugs in cancer cells and promote their growth and metastasis. (B) The green shape shows examples of mechanisms that induce NRF2 activation in cancer cells. Created with BioRender.