The Role of NRF2/KEAP1 Pathway in Glioblastoma: Pharmacological Implications

Shahcheraghi, Seyed Hossein; Salemi, Fateme; Alam, Waqas; Ashworth, Henry; Saso, Luciano; Khan, Haroon; Lotfi, Marzieh

doi:10.1007/s12032-022-01693-0

Cited by 4 publications

(3 citation statements)

References 76 publications

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“…In combination with increased cancer cell motility through EMT, angiogenesis, a critical feature that enhances dissemination of metastatic cancer cells, is increased by NRF2 ( Huang et al, 2021 ; Liu et al, 2021 ; Shahcheraghi et al, 2022 ). This increased angiogenesis has been attributed to NRF2-mediated stabilization of HIF-1α and activation of its transcriptional program ( Ji et al, 2014 ; Zheng et al, 2023 ).…”

Section: Metastasismentioning

confidence: 99%

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Occhiuto

Moerland

Leal

et al. 2023

Molecules and Cells

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The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex. This mini review focuses on key studies describing how the KEAP1/NRF2 pathway affects cancer at different phases. The data compiled suggest that the roles of KEAP1/NRF2 in cancer are highly dependent on context; specifically, the model used (carcinogen-induced vs genetic), the tumor type, and the stage of cancer. Moreover, emerging data suggests that KEAP1/NRF2 is also important for regulating the tumor microenvironment and how its effects are amplified either by epigenetics or in response to co-occurring mutations. Further elucidation of the complexity of this pathway is needed in order to develop novel pharmacological tools and drugs to improve patient outcomes.

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Section: Metastasismentioning

confidence: 99%

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Occhiuto

Moerland

Leal

et al. 2023

Molecules and Cells

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“…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 .…”

Section: Resultsmentioning

confidence: 99%

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

Mandl,

Vettier,

Tessitore

et al. 2023

ACS Appl. Bio Mater.

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Glioblastoma multiforme is an aggressive type of brain cancer with high recurrence rates due to the presence of radioresistant cells remaining after tumor resection. Here, we report the development of an X-ray-mediated photodynamic therapy (X-PDT) system using NaLuF 4 :25% Pr 3+ radioluminescent nanoparticles in conjunction with protoporphyrin IX (PPIX), an endogenous photosensitizer that accumulates selectively in cancer cells. Conveniently, 5-aminolevulinic acid (5-ALA), the prodrug that is administered for PDT, is the only drug approved for fluorescenceguided resection of glioblastoma, enabling dual detection and treatment of malignant cells. NaLuF 4 :Pr 3+ nanoparticles were synthesized and spectroscopically evaluated at a range of Pr 3+ concentrations. This generated radioluminescent nanoparticles with strong emissions from the 1 S 0 excited state of Pr 3+ , which overlaps with the Soret band of PPIX to perform photodynamic therapy. The spectral overlap between the nanoparticles and PPIX improved treatment outcomes for U251 cells, which were used as a model for the thin tumor margin. In addition to sensitizing PPIX to induce X-PDT, our nanoparticles exhibit strong radiosensitizing properties through a radiation dose-enhancement effect. We evaluate the effects of the nanoparticles alone and in combination with PPIX on viability, death, stress, senescence, and proliferation. Collectively, our results demonstrate this as a strong proof of concept for nanomedicine.

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“…Nrf2, as the master mediator of cellular adaptation to redox stress, belongs to the Keap1-Nrf2-ARE (antioxidant response element) signaling pathway. It upregulates AREcontaining genes, such as HO-1, NQO1, GCL, and GST (7). Therefore, Nrf2 plays a pivotal role in cellular responses to oxidative stress, and could help protect cells in normal tissues from harmful stimuli, such as inflammation, trauma, and cancer (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of Nrf2 radiosensitizes glioma cells by inducing redox stress and apoptosis in hypoxia

Tang¹,

Jia²,

Liang³

et al. 2022

Transl Cancer Res TCR

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Background: Radiotherapy remains a mainstream treatment for patients with glioma. Yet intrinsic radioresistance has largely compromised the efficacy of the treatment. Increasing concerns have been raised that overexpression of the Nrf2, along with a hypoxic tumor microenvironment, may have contributed to the deterioration of radiotherapy in tumors. So, this study investigated the role of Nrf2 in the radiation therapy of glioma cells in hypoxia.Methods: To determine the expression levels of Nrf2 and HIF-1α, surgical mastectomy specimens from patients with glioma in our institute were analyzed by immunohistochemical staining. Glioblastoma multiforme (GBM) cell lines U251 and U87 with Nrf2 knocked down were produced by transfection with lentiviral particles. Cell lines were treated with ionizing radiation in hypoxia in vitro, with expression and activity of Nrf2 examined by polymerase chain reaction and western blot. Reactive oxygen species (ROS) generation and cell apoptosis analysis were analyzed by flow cytometry.Results: Nrf2 and its downstream pathway were upregulated in surgical specimens after radiotherapy, verified by GBM cell lines treated with in vitro ionizing radiation in hypoxia. Furthermore, knockdown of Nrf2 could induce the ROS generation and cell apoptosis levels after radiation.Conclusions: Downregulation of Nrf2 could sensitize the lethal effect on GBM cells in vitro by enhancing oxidative stress and apoptosis in hypoxia.

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The Role of NRF2/KEAP1 Pathway in Glioblastoma: Pharmacological Implications

Cited by 4 publications

References 76 publications

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

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

Knockdown of Nrf2 radiosensitizes glioma cells by inducing redox stress and apoptosis in hypoxia

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The Role of NRF2/KEAP1 Pathway in Glioblastoma: Pharmacological Implications

Cited by 4 publications

References 76 publications

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

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

Knockdown of Nrf2 radiosensitizes glioma cells by inducing redox stress and apoptosis in hypoxia

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Resources

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