bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2024‒03‒24
ten papers selected by
Caner Geyik, Istinye University
  1. NRF2 regulates EGF stability through OTUD4 in lung adenocarcinoma.
  2. ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells.
  3. Borax induces ferroptosis of glioblastoma by targeting HSPA5/NRF2/GPx4/GSH pathways.
  4. Design, synthesis and biological evaluation of Nrf2 modulators for the treatment of glioblastoma multiforme.
  5. HDAC1-Mediated Downregulation of NEU1 Exacerbates the Aggressiveness of Cervical Cancer.
  6. NEK2 affects the ferroptosis sensitivity of gastric cancer cells by regulating the expression of HMOX1 through Keap1/Nrf2.
  7. Exploring the NRF2-TP53 Signaling Network Through Machine Learning and Pan-Cancer Analysis: Identifying Potential targets for Cancer Prognosis Related to Oxidative Stress.
  8. Ethanol extract of Eclipta prostrata induces multiple myeloma ferroptosis via Keap1/Nrf2/HO-1 axis.
  9. 4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway.
  10. Combined genetic polymorphisms of the GSTT1 and NRF2 genes increase susceptibility to cisplatin-induced ototoxicity: A preliminary study.
  1. Biochem Biophys Res Commun. 2024 Mar 16. pii: S0006-291X(24)00334-6. [Epub ahead of print]708 149798
    NRF2 regulates EGF stability through OTUD4 in lung adenocarcinoma.
    Shuming Hu, Yuan Yuan, Ruihan Yan, Huikang Xie, Rong Cai, Jiaqian Xu.
      NRF2 (NFE2L2) is a transcription factor mainly for regulating cellular antioxidant response and therefore promotes tumor progression. The target genes of NRF2 also play important roles in cellular processes including glucose metabolism, de novo serine synthesis, iron metabolism, etc. Here, by modulating NRF2 expression in lung adenocarcinoma (LUAD) cells, we showed that NRF2 regulated EGF expression at protein level. Furthermore, EGF was identified as a ubiquitinated protein. We predicted three deubiquitinases of EGF, and OTUD4 had the highest correlation with NRF2 in LUAD among the three. OTUD4 expression was reduced upon NRF2 knocking-down and recovered upon NRF2 rescuing in A549 cells. Then a potential binding site for NRF2 in OTUD4 promoter was searched out. By binding with OTUD4 promoter, NRF2 transcriptionally activated OTUD4, thus promoted EGF deubiquitination and enhanced its stability. More importantly, OTUD4 and NRF2 expression was found being correlated in LUAD patients. The data collectively revealed a novel mechanism of NRF2 regulating on EGF stability through OTUD4 in LUAD.
    Keywords:  EGF; Lung adenocarcinoma; NRF2; OTUD4; Ubiquitination
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149798
  2. Oxid Med Cell Longev. 2024 ;2024 7683793
    ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells.
    Teruaki Takasaki, Yasuyuki Hamabe, Kenta Touchi, Golam Iftakhar Khandakar, Takeshi Ueda, Hitoshi Okada, Kazuko Sakai, Kazuto Nishio, Genzoh Tanabe, Reiko Sugiura.
      The extracellular signal-regulated kinase (ERK) MAPK pathway is dysregulated in various human cancers and is considered an attractive therapeutic target for cancer. Therefore, several inhibitors of this pathway are being developed, and some are already used in the clinic. We have previously identified an anticancer compound, ACA-28, with a unique property to preferentially induce ERK-dependent apoptosis in melanoma cells. To comprehensively understand the biological cellular impact induced by ACA-28, we performed a global gene expression analysis of human melanoma SK-MEL-28 cells exposed to ACA-28 using a DNA microarray. The transcriptome analysis identified nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor that combats oxidative stress, as the most upregulated genetic pathway after ACA-28 treatment. Consistently, ACA-28 showed properties to increase the levels of reactive oxygen species (ROS) as well as Nrf2 protein, which is normally repressed by proteasomal degradation and activated in response to oxidative stresses. Furthermore, the ROS scavenger N-acetyl cysteine significantly attenuated the anticancer activity of ACA-28. Thus, ACA-28 activates Nrf2 signaling and exerts anticancer activity partly via its ROS-stimulating property. Interestingly, human A549 cancer cells with constitutively high levels of Nrf2 protein showed resistance to ACA-28, as compared with SK-MEL-28. Transient overexpression of Nrf2 also increased the resistance of cells to ACA-28, while knockdown of Nrf2 exerted the opposite effect. Thus, upregulation of Nrf2 signaling protects cancer cells from ACA-28-mediated cell death. Notably, the Nrf2 inhibitor ML385 substantially enhanced the cell death-inducing property of ACA-28 in pancreatic cancer cells, T3M4 and PANC-1. Our data suggest that Nrf2 plays a key role in determining cancer cell susceptibility to ACA-28 and provides a novel strategy for cancer therapy to combine the Nrf2 inhibitor and ACA-28.
    DOI:  https://doi.org/10.1155/2024/7683793
  3. J Cell Mol Med. 2024 Apr;28(7): e18206
    Borax induces ferroptosis of glioblastoma by targeting HSPA5/NRF2/GPx4/GSH pathways.
    Cengiz Tuncer, Ceyhan Hacioglu.
      Glioblastoma multiforme (GBM) is a highly aggressive and lethal form of primary brain tumour. Borax has been demonstrated to exhibit anti-cancer activity through cell death pathways. However, the specific impact of borax on ferroptosis in GBM is not well-established, and the underlying regulatory mechanisms remain unclear. Initially, the effective concentration of borax on cell viability and proliferation in U251 and A172 cells was determined. Subsequently, the effects of borax on the wound healing were analysed. Nuclear factor erythroid 2-related factor 2 (NRF2), glutathione peroxidase 4 (GPx4), glutathione (GSH), HSP70 protein 5 (HSPA5), malondialdehyde (MDA) levels and caspase-3/7 activity were determined in borax-treated and untreated cells. Finally, the protein expression levels of HSPA5, NRF2 and GPx4 were analysed. Borax suppressed cell viability and proliferation in U251 and A172 cells in a concentration- and time-dependent manner. In addition, borax treatment decreased GPx4, GSH, HSPA5 and NRF2 levels in U251 and A172 cells while increasing MDA levels and caspase-3/7 activity. Moreover, borax reduced mRNA and protein levels of HSPA5, NRF2 and GPx4 in U251 and A172 cells. Consequently, borax may induce ferroptosis in GBM cells and regulate the associated regulatory mechanisms targeting NRF2 and HSPA5 pathways. This knowledge may contribute to the development of novel therapeutic approaches targeting ferroptosis in GBM and potentially improve patient outcomes.
    Keywords:  HSPA5; NRF2; borax; ferroptosis; glioblastoma multiforme
    DOI:  https://doi.org/10.1111/jcmm.18206
  4. Bioorg Med Chem. 2024 Mar 15. pii: S0968-0896(24)00098-1. [Epub ahead of print]103 117684
    Design, synthesis and biological evaluation of Nrf2 modulators for the treatment of glioblastoma multiforme.
    Huihui Yang, Peilu Song, Baohu Li, Shutang Li, Jinfei Yang.
      Glioblastoma multiforme (GBM) is a prevalent primary brain tumor. However, no specific therapeutic drug has been developed for it. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor involved in the cellular response to oxidative stress. Numerous studies have demonstrated that Nrf2 plays a pivotal role in GBM angiogenesis, and inhibiting Nrf2 can significantly enhance patient prognosis. Using virtual screening technology, we examined our in-house library and identified pinosylvin as a potential compound with high activity. Pinosylvin exhibited robust hydrogen bond and Π-Π interaction with Nrf2. Cell experiments revealed that pinosylvin effectively reduced the proliferation of U87 tumor cells by regulating Nrf2 and demonstrated greater inhibitory activity than temozolomide. Consequently, we believe that this study will offer valuable guidance for the future development of highly efficient therapeutic drugs for GBM.
    DOI:  https://doi.org/10.1016/j.bmc.2024.117684
  5. Crit Rev Eukaryot Gene Expr. 2024 ;34(4): 45-54
    HDAC1-Mediated Downregulation of NEU1 Exacerbates the Aggressiveness of Cervical Cancer.
    Nanzi Xie, Sisi Mei, Changlan Dai, Wei Chen.
      HDAC1 functions as an oncogene in multi-type cancers. This study aimed to investigate the roles of histone deacetylase 1 (HDAC1) in cervical cancer (CC). mRNA expression was determined using reverse transcription quantitative polymerase chain reaction. The protein-protein complexes was analyzed using co-immunoprecipitation assay. The binding sites between NRF2 and NEU1 were confirmed by chromatin immunoprecipitation assay. Cell viability was detected by CCK-8. Cell proliferation was measured using CCK-8 and colony formation assays. Cell migrative and invasive ability were determined using transwell assay. We found that HDAC1 was upregulated in CC patients and cells. Trichostatin A (TSA) treatment decreased the number of colonies and migrated and invaded cells. Moreover, HDAC1 interacted with NRF2 to downregulate NEU1 expression. NEU1 knockdown attenuated the effects of TSA and enhanced the aggressiveness of CC cells. In conclusion, HDAC1 functions as an oncogene in CC. Targeting HDAC1 may be an alternative strategy for CC.
    DOI:  https://doi.org/10.1615/CritRevEukaryotGeneExpr.2023051396
  6. Mol Cell Biochem. 2024 Mar 19.
    NEK2 affects the ferroptosis sensitivity of gastric cancer cells by regulating the expression of HMOX1 through Keap1/Nrf2.
    Jianyong Wu, Desheng Luo, Laizhen Tou, Hongtao Xu, Chuan Jiang, Dan Wu, Haifeng Que, Jingjing Zheng.
      NEK2 is a serine/threonine protein kinase that is involved in regulating the progression of various tumors. Our previous studies have found that NEK2 is highly expressed in gastric cancer and suggests that patients have a worse prognosis. However, its role and mechanism in gastric cancer are only poorly studied. In this study, we established a model of ferroptosis induced by RSL3 or Erastin in AGS cells in vitro, and konckdown NEK2, HOMX1, Nrf2 by siRNA. The assay kit was used to analyzed cell viability, MDA levels, GSH and GSSG content, and FeRhoNox™-1 fluorescent probe, BODIPY™ 581/591 C11 lipid oxidation probe, CM-H2DCFDA fluorescent probe were used to detected intracellular Fe2+, lipid peroxidation, and ROS levels, respectively. Calcein-AM/PI staining was used to detect the ratio of live and dead cells, qRT-PCR and Western blot were used to identify the mRNA and protein levels of genes in cells, immunofluorescence staining was used to analyze the localization of Nrf2 in cells, RNA-seq was used to analyze changes in mRNA expression profile, and combined with the FerrDb database, ferroptosis-related molecules were screened to elucidate the impact of NEK2 on the sensitivity of gastric cancer cells to ferroptosis. We found that inhibition of NEK2 could enhance the sensitivity of gastric cancer cells to RSL3 and Erastin-induced ferroptosis, which was reflected in the combination of inhibition of NEK2 and ferroptosis induction compared with ferroptosis induction alone: cell viability and GSH level were further decreased, while the proportion of dead cells, Fe2+ level, ROS level, lipid oxidation level, MDA level, GSSG level and GSSG/GSH ratio were further increased. Mechanism studies have found that inhibiting NEK2 could promote the expression of HMOX1, a gene related to ferroptosis, and enhance the sensitivity of gastric cancer cells to ferroptosis by increasing HMOX1. Further mechanism studies have found that inhibiting NEK2 could promote the ubiquitination and proteasome degradation of Keap1, increase the level of Nrf2 in the nucleus, and thus promote the expression of HMOX1. This study confirmed that NEK2 can regulate HMOX1 expression through Keap1/Nrf2 signal, and then affect the sensitivity of gastric cancer cells to ferroptosis, enriching the role and mechanism of NEK2 in gastric cancer.
    Keywords:  Ferroptosis; HMOX1; Keap1/Nrf2; NEK2
    DOI:  https://doi.org/10.1007/s11010-024-04960-y
  7. Adv Biol (Weinh). 2024 Mar 22. e2300659
    Exploring the NRF2-TP53 Signaling Network Through Machine Learning and Pan-Cancer Analysis: Identifying Potential targets for Cancer Prognosis Related to Oxidative Stress.
    Yuchen Cao, Ao Fu, Chunjun Liu.
      Oxidative stress (OXS) is closely related to tumor prognosis and immune response, while TP53 integrated with NRF2 is closely associated with the regulation of cancer-related OXS. Hence, constructing a TP53-NRF2 integrated OXS signature of pan-cancer is essential in predicting survival prognosis and facilitating cancer drug treatment. The pan-cancer analysis acquired the Cancer Genome Atlas (TCGA) transcriptome sequencing data from UCSC Xena, which consisted of 33 cancer types (n = 10 440). The Random Forest, Lasso regression, and Cox regression analyses are used to construct an OXS score based on 25 OXS genes. Following this, based on the OXS signature, patients are categorized into low- and high-risk groups. The disparities between the two cohorts regarding survival prognosis, immune infiltration, and drug sensitivity are delved deeply. The expression level of genes is confirmed using immunohistochemistry. The prognosis of pan-cancer patients is adequately predicted by the OXS signature with the assistance of the machine-learning algorithm. A highly accurate nomogram is developed by combining the OXS signature and clinical features. The presence of immune cells indicated that the OXS signature can be associated with the critical pathways of immunotherapy for all types of cancer, and BCL2 showed promising results. Distinct inter-group differences are observed in the OXS signature for frequently utilized antineoplastic medications in clinical settings, including first-line drugs suggested in the guidelines. In summary, by conducting a thorough analysis of OXS genes, a new model based on OXSscore is successfully developed. This model can predict the clinical prognosis and drug sensitivity of pan-cancer with high accuracy. Potential stars in the field of cancer-related anti-OXS may include drugs that target BCL2.
    Keywords:  drug sensitivity; gene signature; machine learning; oxidative stress; pan cancer
    DOI:  https://doi.org/10.1002/adbi.202300659
  8. Phytomedicine. 2024 Feb 01. pii: S0944-7113(24)00066-7. [Epub ahead of print]128 155401
    Ethanol extract of Eclipta prostrata induces multiple myeloma ferroptosis via Keap1/Nrf2/HO-1 axis.
    Wenxia Li, Xuejiao Yin, Hangjie Fu, Jinyuan Liu, Zhiwei Weng, Qingqing Mao, Lijian Zhu, Liuyuan Fang, Zhen Zhang, Bin Ding, Hongyan Tong.
      BACKGROUND: Multiple myeloma (MM) is an incurable hematological malignancy with limited therapeutic efficacy. Eclipta prostrata is a traditional Chinese medicinal plant reported to possess antitumor properties. However, the effects of E. prostrata in MM have not been explored.PURPOSE: The aim of this study was to define the mechanism of the ethanol extract of E. prostrata (EEEP) in treating MM and identify its major components.
    METHODS: The pro-ferroptotic effects of EEEP on cell death, cell proliferation, iron accumulation, lipid peroxidation, and mitochondrial morphology were determined in RPMI-8226 and U266 cells. The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and 4-hydroxynonenal (4HNE) were detected using western blotting during EEEP-mediated ferroptosis regulation. The RPMI-8226 and U266 xenograft mouse models were used to explore the in vivo anticancer effects of EEEP. Finally, high performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry system (UPLC-Q/TOF-MS) were used to identify the major constituents of EEEP.
    RESULTS: EEEP inhibited MM cell growth and induced cell death in vitro and in vivo. By promoting malondialdehyde and Fe2+ accumulation, lipid peroxidation, and GSH suppression, EEEP triggers ferroptosis in MM. Mechanistically, EEEP regulates the Keap1/Nrf2/HO-1 axis and stimulates ferroptosis. EEEP-induced lipid peroxidation and malondialdehyde accumulation were blocked by the Nrf2 activator NK-252. In addition, HPLC and UPLC-Q/TOF-MS analysis elucidated the main components of EEEP, including demethylwedelolactone, wedelolactone, chlorogenic acid and apigenin, which may play important roles in the anti-tumor function of EEEP.
    CONCLUSION: In summary, EEEP exerts its anti-MM function by inducing MM cell death and inhibiting tumor growth in mice. We also showed that EEEP can induce lipid peroxidation and accumulation of ferrous irons in MM cells both in vivo and in vitro, leading to ferroptosis. In addition, this anti-tumor function may be achieved by the EEEP activation of Keap1/Nrf2/HO-1 axis. This is the first study to reveal that EEEP exerts anti-MM activity through the Keap1/Nrf2/HO-1-dependent ferroptosis regulatory axis, making it a promising candidate for MM treatment.
    Keywords:  Eclipta prostrata; Ferroptosis; Keap1/Nrf2/HO-1 axis; Multiple myeloma
    DOI:  https://doi.org/10.1016/j.phymed.2024.155401
  9. J Cell Mol Med. 2024 Apr;28(7): e18207
    4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway.
    Li Zhang, Wenao Song, Hua Li, Xiaolin Cui, Jingyu Ma, Rongrong Wang, Yue Xu, Ming Li, Xiaohui Bai, Dawei Wang, Haihui Sun, Zhiming Lu.
      Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1β. Network Pharmacology and RNA sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by real-time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.
    Keywords:  4-octyl itaconate; NRF2; cisplatin; ferroptosis; ototoxicity
    DOI:  https://doi.org/10.1111/jcmm.18207
  10. Hear Res. 2024 Mar 20. pii: S0378-5955(24)00048-0. [Epub ahead of print]445 108995
    Combined genetic polymorphisms of the GSTT1 and NRF2 genes increase susceptibility to cisplatin-induced ototoxicity: A preliminary study.
    Taro Fujikawa, Taku Ito, Ryuhei Okada, Mitsutaka Sawada, Kaori Mohri, Yumiko Tateishi, Ryosuke Takahashi, Takahiro Asakage, Takeshi Tsutsumi.
      OBJECTIVE: The genotype-phenotype relationship in cisplatin-induced ototoxicity remains unclear. By assessing early shifts in distortion product otoacoustic emission (DPOAE) levels after initial cisplatin administration, we aimed to discriminate patients' susceptibility to cisplatin-induced ototoxicity and elucidate their genetic background.STUDY DESIGN: A prospective cross-sectional study.
    SETTING: Tertiary referral hospital in Japan.
    PATIENTS: Twenty-six patients with head and neck cancer were undergoing chemoradiotherapy with three cycles of 100 mg/m2 cisplatin.
    INTERVENTIONS: Repetitive pure-tone audiometry and DPOAE measurements, and blood sampling for DNA extraction were performed. Patients were grouped into early ototoxicity presence or absence based on whether DPOAE level shifts exceeded the corresponding reference limits of the 21-day test interval.
    MAIN OUTCOME MEASURES: Hearing thresholds after each cisplatin cycle, severity of other adverse events, and polymorphisms in cisplatin-induced ototoxicity-associated genes were compared.
    RESULTS: Early ototoxicity was present in 14 and absent in 12 patients. Ototoxicity presence on DPOAEs was associated with greater progression of hearing loss in frequencies ≥2 kHz throughout therapy and with higher ototoxicity grades compared with ototoxicity absence. Ototoxicity was further associated with grade ≥2 nausea. Ototoxicity presence was genetically associated with the GSTT1 null genotype and G-allele of NFE2L2 rs6721961, whereas ototoxicity absence was associated with the GSTM1 null genotype. Dose-dependent progression of hearing loss was the greatest in the combined genotype pattern of GSTT1 null and the T/G or G/G variants of rs6721961.
    CONCLUSION: Early DPOAE changes reflected genetic vulnerability to cisplatin-induced ototoxicity. Hereditary insufficiency of the antioxidant defense system causes severe cisplatin-induced hearing loss and nausea.
    Keywords:  Cisplatin-induced ototoxicity; DPOAEs; GSTT1; NRF2; Polygenic inheritance; Reference limits
    DOI:  https://doi.org/10.1016/j.heares.2024.108995
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