The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

Glorieux, Christophe; Enríquez, Cinthya; González, Constanza; Aguirre-Martínez, Gabriela; Buc Calderon, Pedro

doi:10.3390/antiox13010070

Cited by 14 publications

(2 citation statements)

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“…DNA oxidation results in the accumulation of mutations, which can cause the development of malignancies [ 111 , 115 ]. If regulation of the redox balance is disrupted due to alterations in the Nrf2/Keap1 signaling pathway, it can lead to increased oxidative damage and mutations, thereby raising the risk of tumor development [ 115 , 116 , 117 , 118 ]. On the other hand, Nrf2 protects cells by preventing the accumulation of ROS and thus oxidative stress.…”

Section: Oxidative Signaling Modulates Signal Cascades and The Expres...mentioning

confidence: 99%

“…In this context, the deregulation of Nrf2 and/or Keap1 is detrimental [ 118 , 119 , 120 , 121 ] as the induction of antioxidant genes by Nrf2 enables the survival of these malignant cells, which would otherwise die from oxidative damage. Additionally, resistance to chemotherapy increases because many chemotherapeutic agents work by shifting the redox balance and generating ROS [ 116 , 118 , 119 ]. Thus, Nrf2 is indeed a double-edged sword.…”

Section: Oxidative Signaling Modulates Signal Cascades and The Expres...mentioning

confidence: 99%

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Unraveling the Role of Reactive Oxygen Species in T Lymphocyte Signaling

Gülow,

Tümen,

Heumann

et al. 2024

IJMS

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Reactive oxygen species (ROS) are central to inter- and intracellular signaling. Their localized and transient effects are due to their short half-life, especially when generated in controlled amounts. Upon T cell receptor (TCR) activation, regulated ROS signaling is primarily initiated by complexes I and III of the electron transport chain (ETC). Subsequent ROS production triggers the activation of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2), prolonging the oxidative signal. This signal then engages kinase signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway and increases the activity of REDOX-sensitive transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). To limit ROS overproduction and prevent oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant proteins such as superoxide dismutases (SODs) finely regulate signal intensity and are capable of terminating the oxidative signal when needed. Thus, oxidative signals, such as T cell activation, are well-controlled and critical for cellular communication.

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Section: Oxidative Signaling Modulates Signal Cascades and The Expres...mentioning

confidence: 99%

Section: Oxidative Signaling Modulates Signal Cascades and The Expres...mentioning

confidence: 99%

Unraveling the Role of Reactive Oxygen Species in T Lymphocyte Signaling

Gülow,

Tümen,

Heumann

et al. 2024

IJMS

View full text Add to dashboard Cite

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Solasodine Downregulates ABCB1 Overexpression in Multidrug Resistant Cancer Cells Via Inhibiting Nrf2/Keap1 Signaling Pathway

Bharathiraja,

Baskar,

Prasad

2024

J of Cellular Biochemistry

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Multidrug‐resistant (MDR) cancer cells maintain redox homeostasis to eliminate oxidative stress‐mediated cell death. This study explores the effects of solasodine on regulating P‐glycoprotein (P‐gp) expression through the Nrf2/Keap1 signaling pathway and oxidative stress‐induced sensitization of drug‐resistant cancer cells to chemotherapeutics. Initially, the oxidative stress indicators such as intracellular ROS generation, the levels of 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) and gamma‐H2AX (γ‐H2AX) in the KBChR‐8‐5 drug‐resistant cells were measured. Additionally, the protein expression levels of Nuclear factor erythroid 2‐related factor 2 (Nrf‐2), Kelch‐like ECH‐associated protein 1 (Keap1), and ATP Binding Cassette Subfamily B Member 1 (ABCB1)/P‐gp were measured at various concentrations of solasodine (1, 5, & 10 µM) through immunofluorescence and western blot analysis. The antioxidant activities in the KBChR‐8‐5 cells were assessed using established protocols. In this investigation, the treatment with solasodine and doxorubicin combination showed a notable increase in intracellular ROS generation in KBChR‐8‐5 cells. Furthermore, this combination treatment led to enhanced nuclear condensation, elevated levels of 8‐OHdG, and increased γ‐H2AX foci formation in the KBChR‐8‐5 cells. Solasodine treatment effectively inhibited the nuclear translocation of Nrf2 and activation of the ABCB1 gene, consequently preventing overexpression of P‐gp in KBChR‐8‐5 cells. Additionally, the combination therapy increased the lipid peroxidation levels while simultaneously reducing the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and the levels of glutathione (GSH). These results demonstrated that solasodine disrupts redox balance, and overcomes drug resistance by downregulating P‐gp via regulating Nrf2/Keap1 signaling pathway in MDR cancer cells.

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