bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2024–06–02
eight papers selected by
Caner Geyik, Istinye University
  1. Targeting Nrf2 signaling pathways in the role of bladder cancer: From signal network to targeted therapy.
  2. The EGR1/miR-139/NRF2 axis orchestrates radiosensitivity of non-small-cell lung cancer via ferroptosis.
  3. [Stellera chamaejasme against multidrug resistance of triple-negative breast cancer MDA-MB-231 cell through Nrf2].
  4. Ionizing Radiation-treated NRF2-deficient Cancer Cells Promote Type I Interferon Signaling in Immune Cells.
  5. Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP-J/NRF2/FDX1 pathway.
  6. CSF2 Impairs Nrf2 Signaling through the Akt/Mtor Pathway in the Development of Bladder Cancer.
  7. CARD11-BCL10-MALT1 complex-dependent MALT1 activation facilitates myocardial oxidative stress in doxorubicin-treated mice via enhancing k48-linked ubiquitination of Nrf2.
  8. Mitigation of cisplatin-induced cardiotoxicity by Isorhamnetin: Mechanistic insights into oxidative stress, inflammation, and apoptosis modulation.
  1. Biomed Pharmacother. 2024 May 30. pii: S0753-3322(24)00713-3. [Epub ahead of print]176 116829
    Targeting Nrf2 signaling pathways in the role of bladder cancer: From signal network to targeted therapy.
    Liang Wu, Zhao Hu, Xiao-Fen Song, Yu-Jian Liao, Jiang-Huan Xiahou, Yuan Li, Zhong-Hua Zhang.
      Bladder cancer (BC) is the most common malignancy of the urinary system and often recurs after tumor removal and/or is resistant to chemotherapy. In cancer cells, the activity of the signaling pathway changes significantly, affecting a wide range of cell activities from growth and proliferation to apoptosis, invasion and metastasis. Nrf2 is a transcription factor that plays an important role in cellular defense responses to a variety of cellular stresses. There is increasing evidence that Nrf2 acts as a tumor driver and that it is involved in the maintenance of malignant cell phenotypes. Abnormal expression of Nrf2 has been found to be common in a variety of tumors, including bladder cancer. Over-activation of Nrf2 can lead to DNA damage and the development of bladder cancer, and is also associated with various pathological phenomena of bladder cancer, such as metastasis, angiogenesis, and reduced toxicity and efficacy of therapeutic anticancer drugs to provide cell protection for cancer cells. However, the above process can be effectively inhibited or reversed by inhibiting Nrf2. Therefore, Nrf2 signaling may be a potential targeting pathway for bladder cancer. In this review, we will characterize this signaling pathway and summarize the effects of Nrf2 and crosstalk with other signaling pathways on bladder cancer progression. The focus will be on the impact of Nrf2 activation on bladder cancer progression and current therapeutic strategies aimed at blocking the effects of Nrf2. To better determine how to promote new chemotherapy agents, develop new therapeutic agents, and potential therapeutic targets.
    Keywords:  Bladder cancer; Drug resistance; Nuclear factor erythrocyte 2-associated factor 2 (Nrf2); Oxidative stress; Therapeutic strategy
    DOI:  https://doi.org/10.1016/j.biopha.2024.116829
  2. Cancer Lett. 2024 May 29. pii: S0304-3835(24)00394-X. [Epub ahead of print] 217000
    The EGR1/miR-139/NRF2 axis orchestrates radiosensitivity of non-small-cell lung cancer via ferroptosis.
    Lu Zhang, Yihan Xu, Zeyuan Cheng, Jinlin Zhao, Meixi Wang, Yanchen Sun, Zeyun Mi, Zhiyong Yuan, Zhiqiang Wu.
      Radiotherapy is one of the predominant treatment modalities for almost all kinds of malignant cancers, including non-small cell lung cancer (NSCLC). Increasing evidence shows that ionizing radiation (IR) induces reactive oxygen species (ROS) leading to lipid peroxidation and subsequently ferroptosis of cancer cells. However, cancer cells evolve multiple mechanisms against ROS biology resulting in resistance to ferroptosis and radiotherapy, of which NRF2 signaling is one of the most studied. In the current research, we identified that microRNA-139 (miR-139) could be a novel radiosensitizer for NSCLC by inhibiting NRF2 signaling. We found that miR-139 possessed great potential as a diagnostic biomarker for NSCLC and multiple other types of cancer. Overexpression of miR-139 increased radiosensitivity of NSCLC cells in vitro and in vivo. MiR-139 directly targeted cJUN and KPNA2 to impair NRF2 signaling resulting in enhanced IR-induced lipid peroxidation and cellular ferroptosis. We proved KPNA2 to be a binding partner of NRF2 that involved in nuclear translocation of NRF2. Moreover, we found that IR induced miR-139 expression through transcriptional factor EGR1. EGR1 bound to the promoter region and transactivated miR-139. Overall, our findings elucidated the effect of EGR1/miR-139/NRF2 in IR-induced ferroptosis of NSCLC cells and provided theoretical support for the potential diagnostic biomarkers and therapeutic targets for the disease.
    Keywords:  Ferroptosis; NRF2 signaling; Non-small cell lung cancer; ROS; Radiotherapy; microRNA
    DOI:  https://doi.org/10.1016/j.canlet.2024.217000
  3. Zhongguo Zhong Yao Za Zhi. 2024 Apr;49(8): 2222-2229
    [Stellera chamaejasme against multidrug resistance of triple-negative breast cancer MDA-MB-231 cell through Nrf2].
    Rui Zeng, Xiao-Xuan Wang, Xi-He Cui, Qing Yang, Xiao-Xin Zhu, Ya-Jie Wang.
      This study aims to investigate the effect and mechanism of Stellera chamaejasme extract(SCL) on multidrug resistance(MDR) in breast cancer. Human triple-negative breast cancer cell line MDA-MB-231 and its adriamycin-resistant cell line MDA-MB-231/ADR were used in the experiment. Cell viability was detected by methyl thiazolyl tetrazolium(MTT) assay, and cell apoptosis was detected by DAPI staining and Annexin-V/Pi double staining. Western blot(WB) was used to detect the expression levels of Keap1, Nrf2, HO-1, Bcl-2, Bax, caspase-9, and caspase-3. Immunofluorescence staining was used to observe the distribution of Nrf2 in the cell, and flow cytometry was used to detect the level of reactive oxygen species(ROS) in the cell. The results showed that the resis-tance factor of SCL was 0.69, and that of adriamycin and paclitaxel was 8.40 and 16.36, respectively. DAPI staining showed that SCL could cause nuclear shrinkage and fragmentation of breast cancer cells. Annexin-V/Pi double staining showed that the average apoptosis rate of the drug-resistant cells was 32.64% and 50.29%, respectively under medium and high doses of SCL. WB results showed that SCL could significantly reduce the expression levels of anti-apoptotic proteins Bcl-2, caspase-9, and caspase-3 and significantly increase the expression level of pro-apoptotic protein Bax. Further studies showed that SCL could significantly promote the expression of Keap1, significantly inhibit the expression of Nrf2 and HO-1, and significantly reduce the expression level of Nrf2 in the nucleus. Correspondingly, flow cytometry showed that the intracellular ROS level was significantly increased. In conclusion, SCL can significantly inhibit the proliferation of MDA-MB-231 multidrug-resistant cells of triple-negative breast cancer and cause cell apoptosis, and the mechanism is related to inhibiting Keap1/Nrf2 signaling pathway, leading to ROS accumulation in drug-resistant cells and increasing the expression of apoptosis-related proteins.
    Keywords:  Nrf2; Stellera chamaejasme extract; antioxidant; apoptosis; multidrug resistance in breast cance
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20231212.704
  4. Anticancer Res. 2024 Jun;44(6): 2577-2585
    Ionizing Radiation-treated NRF2-deficient Cancer Cells Promote Type I Interferon Signaling in Immune Cells.
    Hye-Ran Seo, Hyo Jung Kim, Hwani Ryu, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn.
       BACKGROUND/AIM: Nuclear factor erythroid-derived 2-related factor-2 (NRF2) is a transcription factor that regulates stress response genes. It negatively regulates the immune system by acting as a transcriptional repressor of inflammatory genes or suppressing type I interferon (IFN) production pathways. NRF2 is often over-expressed in some tumors, including non-small cell lung cancer, and modulates these tumors via an immune-cold microenvironment. Thus, strategies to convert cold tumors into hot tumors are effective for cancer treatment.
    MATERIALS AND METHODS: NRF2 was knocked-down or over-expressed in human cancer cells (A549, HeLa, H1299, H1650) and mouse mammary adenocarcinoma TS/A cells. Cells were irradiated or transfected with poly(I:C), and changes in type I IFN levels were examined using quantitative real-time polymerase chain reaction and western blotting. Cytosolic DNA was assayed via PicoGreen staining and immune and cancer cells were co-cultured.
    RESULTS: Regulation of NRF2 expression altered type I IFN levels in the human lung cancer cell line A549 and several solid tumors. Down-regulation of NRF2 resulted in increased levels of cytosolic DNA and activated the cGAS-STING pathway. We confirmed that type I IFN was induced in NRF2-down-regulated tumor cells using ionizing radiation (IR). Furthermore, when dendritic cells and macrophages were co-cultured with IR-exposed NRF2 knockdown tumor cells, the immune cells produced more IFNB1 and CXCL10.
    CONCLUSION: The immunosuppressive tumor cell environment is improved by NRF2 down-regulation, and IR treatment may promote immune cell signaling activation.
    Keywords:  Ionizing radiation; NRF2; cancer immune response; type I interferon
    DOI:  https://doi.org/10.21873/anticanres.17063
  5. Mol Carcinog. 2024 May 27.
    Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP-J/NRF2/FDX1 pathway.
    Min-Jie Zhang, Mengna Shi, Yang Yu, Rongying Ou, Ren-Shan Ge, Ping Duan.
      Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1-propyl-3,5-bis(2-bromobenzylidene)-4-piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit-8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC50 value of 4.16 μM for Hela cells and 3.78 μM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP-J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP-J resulted in the enrichment of RBP-J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer.
    Keywords:  curcuminoid; ferredoxin 1; reactive oxidative species; thioredoxin 1
    DOI:  https://doi.org/10.1002/mc.23735
  6. J Cancer. 2024 ;15(11): 3242-3253
    CSF2 Impairs Nrf2 Signaling through the Akt/Mtor Pathway in the Development of Bladder Cancer.
    Xi Yu, Shenglan Li, Shuai Ke, Chenglin Ye, Qinghua Wang, Huaxin Wang, Lei Wang.
      Bladder Cancer (BCa) is one of the most common cancers of the urinary system. Colony-stimulating factor 2 (CSF2) is involved in many cancers, but not BCa. We investigated the effect of CSF2 on BCa in this study and the underlying molecular mechanisms. CSF2 mRNA levels in BCa were analyzed using the Cancer Genome Atlas (TCGA) database. Western blot was conducted to verify CSF2 expression in BCa tissue samples and cell lines. The effect of CSF2 on the growth of BCa cells was assessed by CCK8 and colony formation. To determine the migration and invasion capabilities of BCa cells, transwell analysis and wound healing assays were conducted. Next, western blot was used to explore the underlying mechanism. In the end, a xenografted BCa mouse model was established to examine the effects of CSF2 on tumorigenesis in vivo. Results showed that CSF2 mRNA was upregulated in BCa samples. Knocking down CSF2 significantly inhibited the proliferation and tumorigenesis of BCa cells in vitro and in vivo. Mechanism analysis revealed that CSF2 knockdown inhibited the proliferation and invasion of BCa cells via AKT/mTOR signaling. Based on these results, CSF2 promotes the proliferation and tumorigenesis of BCa.
    Keywords:  AKT/mTOR pathway; CSF2; EMT; Nrf2; bladder cancer
    DOI:  https://doi.org/10.7150/jca.94343
  7. Antioxid Redox Signal. 2024 May 30.
    CARD11-BCL10-MALT1 complex-dependent MALT1 activation facilitates myocardial oxidative stress in doxorubicin-treated mice via enhancing k48-linked ubiquitination of Nrf2.
    Li-Qun Lu, Ming-Rui Li, Xu-Yan Liu, Dan Peng, Hong-Rui Liu, Xiao-Jie Zhang, Xiu-Ju Luo, Jun Peng.
       AIMS: Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) contributes to doxorubicin (DOX)-induced myocardial oxidative stress, and inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) increased Nrf2 protein level in rat heart suffered ischemia/reperfusion, indicating a connection between MALT1 and Nrf2. This study aims to explore the role of MALT1 in DOX-induced myocardial oxidative stress and the underlying mechanisms.
    RESULTS: The mice received a single injection of DOX (15 mg/kg, i.p.) to induce myocardial oxidative stress, evidenced by increases in the levels of reactive oxidative species while decreases in the activities of anti-oxidative enzymes, concomitant with a down-regulation of Nrf2; these phenomena were reversed by MALT1 inhibitor. Similar phenomena were observed in DOX-induced oxidative stress in cardiomyocytes. Mechanistically, knockdown or inhibition of MALT1 notably attenuated the interaction between Nrf2 and MALT1, and decreased the k48-linked ubiquitination of Nrf2. Furthermore, inhibition or knockdown of calcium/calmodulin-dependent protein kinase II (CaMKII-δ) reduced the phosphorylation of caspase recruitment domain-containing protein 11 (CARD11), and subsequently disrupted the assembly of CARD11, B-cell lymphoma 10 (BCL10) and MALT1 (CBM) complex, and reduced the MALT1-dependent k48-linked ubiquitination of Nrf2 in DOX-treated mice or cardiomyocytes.
    INNOVATION AND CONCLUSION: The E3 ubiquitin ligase function of MALT1 accounts for the down-regulation of Nrf2 and aggravation of myocardial oxidative stress in DOX-treated mice, and CaMKII-δ-dependent phosphorylation of CARD11 triggered the assembly of CBM complex and subsequent activation of MALT1.
    DOI:  https://doi.org/10.1089/ars.2023.0543
  8. Toxicol Rep. 2024 Jun;12 564-573
    Mitigation of cisplatin-induced cardiotoxicity by Isorhamnetin: Mechanistic insights into oxidative stress, inflammation, and apoptosis modulation.
    Rawan Abudalo, Omar Gammoh, Sara Altaber, Yousra Bseiso, Esam Qnais, Mohammed Wedyan, Muna Oqal, Abdelrahim Alqudah.
      The flavonoid compound Isorhamnetin (IRMN) is known for its considerable pharmacological properties, which include antioxidant and anti-inflammatory effects, as well as significant protective actions on heart health. However, the potential of IRMN to guard against heart damage caused by cisplatin (CP), a common chemotherapeutic agent, and the specific mechanisms involved, remain unexplored areas. This research was designed to investigate how IRMN counters CP-induced heart toxicity. In our study, mice were orally given IRMN at 50 or 150 mg/kg/day for a week, followed by CP injections (5 mg/kg/day) on the third and sixth days. The animals were euthanized under sodium pentobarbital anesthesia (50 mg/kg, intraperitoneally) on the eighth day to collect blood and heart tissues for further examination. Our findings reveal that IRMN administration significantly reduced the heart damage and the elevation of heart injury markers such as cardiac troponin I, creatine kinase, and lactate dehydrogenase induced by CP. IRMN also effectively lowered oxidative stress markers, including reactive oxygen species and malondialdehyde, while boosting ATP production and antioxidants like superoxide dismutase, catalase, and glutathione. The compound's capability to diminish the levels of pro-inflammatory cytokines like tumor necrosis factor-alpha and interleukin-6, alongside modulating apoptosis-regulating proteins (enhancing Bcl-2 while suppressing Bax and Caspase-3 expression), further underscores its cardioprotective effect. Notably, IRMN modulated the p62-Keap1-Nrf2 signaling pathway, suggesting a mechanism through which it exerts its protective effects against CP-induced cardiac injury. These insights underscore the potential of IRMN as an effective adjunct in cancer therapy, offering a strategy to mitigate the cardiotoxic side effects of cisplatin.
    Keywords:  Apoptosis; Cardiotoxicity; Cisplatin; Inflammation; Isorhamnetin; Nrf2; Oxidative stress
    DOI:  https://doi.org/10.1016/j.toxrep.2024.05.003
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