NRF2‐dependent stress defense in tumor antioxidant control and immune evasion

Angeli, José Pedro Friedmann; Meierjohann, Svenja

doi:10.1111/pcmr.12946

Cited by 24 publications

(15 citation statements)

References 119 publications

(147 reference statements)

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“…To further explore the function of NFE2L3, we combined data from public databases to analyze the possible biological functions of NFE2L3 in the body from the point of view of bioinformatics. Increasing evidence indicates that NFE2L2, a protein that is homologous to the NFE2L3 transcription factor, is involved in immune evasion and is associated with immune infiltration of low-grade gliomas [ 31 , 32 ]. We then used TIMER 2.0 ( http://timer.comp-genomics.org ) to predict the association between NFE2L3 expression and immune cells.…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of NFE2L3 promotes the development of gastric cancer through epithelial-mesenchymal transformation

Wang

Fang

et al. 2021

Bioengineered

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Gastric cancer (GC) is a malignant tumor with high mortality, but research on its molecular mechanisms remain limited. This study is the first to explore the biological role of nuclear factor NFE2L3 (nuclear factor, erythroid 2 like 3) in GC. We used Western blot and RT–qPCR to detect gene expression at the protein or mRNA level. Short hairpin RNA (shRNA) transfection was used to inhibit NFE2L3 expression. CCK-8 and colony formation assays were used to detect cell proliferation. Cell migration, invasion, cell cycle and apoptosis were detected by Transwell assays and flow cytometry. The results showed that NFE2L3 was highly expressed in gastric cancer tissues and promoted gastric cancer cell proliferation and metastasis. Inhibiting NFE2L3 expression blocks the cell cycle and increases the proportion of apoptotic cells, whereas NFE2L3 expression promotes the epithelial-mesenchymal transformation (EMT) process. In summary, NFE2L3 is highly expressed in gastric cancer and promotes gastric cancer cell proliferation and metastasis and the EMT process.

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Section: Discussionmentioning

confidence: 99%

Elevated expression of NFE2L3 promotes the development of gastric cancer through epithelial-mesenchymal transformation

Wang

Fang

et al. 2021

Bioengineered

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“…High Nrf2 tumors were highly infiltrated by immune cells (CD8+, CD4+, and DCs) and stromal cells (adipocytes, fibroblasts, and keratinocytes [124]. In contrast, the negative effects of Nrf2 expression have been reported for glioblastoma [125] and lung adenocarcinoma [126]. Tumor entities presenting oncogenic activation of Nrf2 were found to be associated with drug resistance and immune evasion [125,126].…”

Section: Mitohormesis Macrophages and Case Reportsmentioning

confidence: 99%

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

Schirrmacher¹

2021

Biomedicines

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A dose-response relationship to stressors, according to the hormesis theory, is characterized by low-dose stimulation and high-dose inhibition. It is non-linear with a low-dose optimum. Stress responses by cells lead to adapted vitality and fitness. Physical stress can be exerted through heat, radiation, or physical exercise. Chemical stressors include reactive species from oxygen (ROS), nitrogen (RNS), and carbon (RCS), carcinogens, elements, such as lithium (Li) and silicon (Si), and metals, such as silver (Ag), cadmium (Cd), and lead (Pb). Anthropogenic chemicals are agrochemicals (phytotoxins, herbicides), industrial chemicals, and pharmaceuticals. Biochemical stress can be exerted through toxins, medical drugs (e.g., cytostatics, psychopharmaceuticals, non-steroidal inhibitors of inflammation), and through fasting (dietary restriction). Key-lock interactions between enzymes and substrates, antigens and antibodies, antigen-presenting cells, and cognate T cells are the basics of biology, biochemistry, and immunology. Their rules do not obey linear dose-response relationships. The review provides examples of biologic stressors: oncolytic viruses (e.g., immuno-virotherapy of cancer) and hormones (e.g., melatonin, stress hormones). Molecular mechanisms of cellular stress adaptation involve the protein quality control system (PQS) and homeostasis of proteasome, endoplasmic reticulum, and mitochondria. Important components are transcription factors (e.g., Nrf2), micro-RNAs, heat shock proteins, ionic calcium, and enzymes (e.g., glutathion redox enzymes, DNA methyltransferases, and DNA repair enzymes). Cellular growth control, intercellular communication, and resistance to stress from microbial infections involve growth factors, cytokines, chemokines, interferons, and their respective receptors. The effects of hormesis during evolution are multifarious: cell protection and survival, evolutionary flexibility, and epigenetic memory. According to the hormesis theory, this is true for the entire biosphere, e.g., archaia, bacteria, fungi, plants, and the animal kingdoms.

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“…Nuclear factor erythroid 2-related factor 2 (Nrf2) / phosphatase and tensin homologue (PTEN) plays an important role in antitumor immunity [ 27 , 28 ]. We found morphine increased Nrf2 and decreased PTEN expression in A549 and H460 cells, while naringin (PTEN activator, 150 μM) decreased MAEL expression induced by morphine (Fig.…”

Section: Resultsmentioning

confidence: 99%

Morphine suppresses the immune function of lung cancer by up-regulating MAEL expression

Wang¹,

Liu

Tang³

et al. 2022

BMC Pharmacol Toxicol

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Background Patients with cancer rely on morphine for analgesia, while studies have indicated morphine can induce immunosuppression in cancer. Therefore, investigating the immunosuppressive roles and molecular mechanism of morphine on lung cancer progression is imperative. Methods Lactate dehydrogenase (LDH) release assay was used to determine the cytotoxicity of morphine to lung cancer cells. The percentage of CD4+ and CD8+ T cells was detected by flow cytometry. In addition, Maelstrom (MAEL), Nrf2, and PTEN were determined by western blot and RT-qPCR. Immune factors programmed death-ligand 1 (PD-L1), transforming growth factor (TGF-β), interleukin (IL)-10, and IL-2 were determined by western blot and ELISA assay. Results Morphine increased the levels of PD-L1, TGF-β, and IL-10, while decreased IL-2 level. Morphine enhanced MAEL expression in A549 cells and H460 cells. Morphine up-regulated Nrf2 and down-regulated PTEN, and morphine-induced MAEL up-regulation was reversed by PTEN. However, MAEL silencing inhibited the enhanced effects of morphine on cell viability and proliferation of A549 cells. Furthermore, morphine treatment reduced the LDH release and the percentage of CD8+ T cells, and increased the ratio of CD4+/CD8+ T cells and tumor weight. Meanwhile, MAEL silencing reversed the effects of morphine on immune factors (PD-L1, TGF-β, IL-10, and IL-2), the percentage of CD8+ T cells, and the ratio of CD4+/CD8+ T cells. Conclusion Morphine activated MAEL in lung cancer cells by Nrf2/PTEN pathway and regulated the immune factors, thereby promoting tumor immune escape.

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NRF2‐dependent stress defense in tumor antioxidant control and immune evasion

Cited by 24 publications

References 119 publications

Elevated expression of NFE2L3 promotes the development of gastric cancer through epithelial-mesenchymal transformation

Elevated expression of NFE2L3 promotes the development of gastric cancer through epithelial-mesenchymal transformation

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

Morphine suppresses the immune function of lung cancer by up-regulating MAEL expression

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