bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2024–07–21
twelve papers selected by
Caner Geyik, Istinye University
  1. A core NRF2 gene set defined through comprehensive transcriptomic analysis predicts selective drug resistance and poor multi-cancer prognosis.
  2. Ferroptosis regulation by Cap'n'collar family transcription factors.
  3. Regulation of Keap1-Nrf2 signaling in health and diseases.
  4. The regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy.
  5. Nrf2 affects DNA damage repair and cell apoptosis through regulating HR and the intrinsic Caspase-dependent apoptosis pathway in TK6 cells exposed to hydroquinone.
  6. Citraconate promotes the malignant progression of colorectal cancer by inhibiting ferroptosis.
  7. Ethnic Differences, Lung Cancer Risk, and Association of NRF2 Gene Polymorphism with Gemcitabine-Based Chemotherapy.
  8. EGR1 Promotes Erastin-induced Ferroptosis Through Activating Nrf2-HMOX1 Signaling Pathway in Breast Cancer Cells.
  9. Excess endocrine growth hormone in acromegaly promotes the aggressiveness and metastasis of triple-negative breast cancer.
  10. A novel antitumor mechanism of triptonide in colorectal cancer: inducing ferroptosis via the SLC7A11/GPX4 axis.
  11. Three Ru(II) complexes modulate the antioxidant transcription factor Nrf2 to overcome cisplatin resistance.
  12. Sphingosine 1-phosphate combining with S1PR4 promotes regulatory T cell differentiation related to FAO through Nrf2/PPARα.
  1. Antioxid Redox Signal. 2024 Jul 19.
    A core NRF2 gene set defined through comprehensive transcriptomic analysis predicts selective drug resistance and poor multi-cancer prognosis.
    George Luo, Harshita Kumar, Kristin Alridge, Stevie Rieger, Eunhyang Han, Ethan Jiang, Ernest Chan, Ahmed Soliman, Haider Mahdi, John J Letterio.
       AIMS: The NRF2-KEAP1 pathway plays an important role in the cellular response to oxidative stress but may also contribute to metabolic changes and drug resistance in cancer. However, despite its pervasiveness and important role, most of NRF2 target genes are defined in context specific experiments and analysis, making it difficult to translate from one situation to another. Our study investigates whether a core NRF2 gene signature can be derived and used to represent NRF2 in various contexts, allowing better reproducibility and understanding of NRF2 activation.
    RESULTS: We define a core set of 14 upregulated NRF2 target genes from seven RNA-sequencing datasets that we generated and analyzed. This NRF2 gene signature was validated using analyses of published datasets and gene sets. An NRF2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and necrosulfonamide but not to paclitaxel or bardoxolone methyl. We validated these findings in our KEAP1 knockout cancer cell lines. Finally, our NRF2 score is prognostic for cancer survival and validated in additional independent cohorts for lung adenocarcinoma and also novel cancers types not associated with NRF2-KEAP1 mutations such as clear cell renal carcinoma, hepatocellular carcinoma, and acute myeloid leukemia.
    INNOVATION AND CONCLUSIONS: These analyses define a core NRF2 gene signature that is robust, versatile, and useful for evaluating NRF2 activity and for predicting drug resistance and cancer prognosis. Using this gene signature, we uncover novel selective drug resistance and cancer prognosis associated with NRF2 activation.
    DOI:  https://doi.org/10.1089/ars.2023.0409
  2. J Biol Chem. 2024 Jul 16. pii: S0021-9258(24)02084-2. [Epub ahead of print] 107583
    Ferroptosis regulation by Cap'n'collar family transcription factors.
    Magdalena B Murray, Scott J Dixon.
      Ferroptosis is an iron-dependent cell death mechanism that may be important to prevent tumor formation and useful as a target for new cancer therapies. Transcriptional networks play a crucial role in shaping ferroptosis sensitivity by regulating the expression of transporters, metabolic enzymes, and other proteins. The Cap'n'collar (CNC) protein nuclear factor erythroid 2 like 2 (NFE2L2, also known as NRF2) is a key regulator of ferroptosis in many cells and contexts. Emerging evidence indicates that the related CNC family members BTB and CNC homology 1 (BACH1) and nuclear factor erythroid 2 like 1 (NFE2L1) also have non-redundant roles in ferroptosis regulation. Here, we comprehensively review the role of CNC transcription factors in governing cellular sensitivity to ferroptosis. We describe how CNC family members regulate ferroptosis sensitivity through modulation of iron, lipid, and redox metabolism. We also use examples of ferroptosis regulation by CNC proteins to illustrate the flexible and highly context-dependent nature of the ferroptosis mechanism between cells and conditions.
    Keywords:  BACH1; NFE2L1; NRF2; Nuclear factor 2 (erythroid‐derived 2‐like factor) (NFE2L2); Oxidative stress; glycosylation; iron metabolism; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.jbc.2024.107583
  3. Mol Biol Rep. 2024 Jul 13. 51(1): 809
    Regulation of Keap1-Nrf2 signaling in health and diseases.
    Jiang-Ling Xiao, Heng-Yuan Liu, Chen-Chen Sun, Chang-Fa Tang.
      Nuclear factor erythroid 2-related factor 2 (Nrf2) functions as a central regulator in modulating the activities of diverse antioxidant enzymes, maintaining cellular redox balance, and responding to oxidative stress (OS). Kelch-like ECH-associated protein 1 (Keap1) serves as a principal negative modulator in controlling the expression of detoxification and antioxidant genes. It is widely accepted that OS plays a pivotal role in the pathogenesis of various diseases. When OS occurs, leading to inflammatory infiltration of neutrophils, increased secretion of proteases, and the generation of large quantities of reactive oxygen radicals (ROS). These ROS can oxidize or disrupt DNA, lipids, and proteins either directly or indirectly. They also cause gene mutations, lipid peroxidation, and protein denaturation, all of which can result in disease. The Keap1-Nrf2 signaling pathway regulates the balance between oxidants and antioxidants in vivo, maintains the stability of the intracellular environment, and promotes cell growth and repair. However, the antioxidant properties of the Keap1-Nrf2 signaling pathway are reduced in disease. This review overviews the mechanisms of OS generation, the biological properties of Keap1-Nrf2, and the regulatory role of its pathway in health and disease, to explore therapeutic strategies for the Keap1-Nrf2 signaling pathway in different diseases.
    Keywords:  Diseases; Healthy; Keap1-Nrf2 signaling pathway; Oxidation and antioxidant; Regulatory mechanism
    DOI:  https://doi.org/10.1007/s11033-024-09771-4
  4. Acta Pharmacol Sin. 2024 Jul 17.
    The regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy.
    Xin Jiang, Min Yu, Wei-Kai Wang, Li-Yuan Zhu, Xian Wang, Hong-Chuan Jin, Li-Feng Feng.
      Ferroptosis is an iron-dependent programmed cell death process that involves lipid oxidation via the Fenton reaction to produce lipid peroxides, causing disruption of the lipid bilayer, which is essential for cellular survival. Ferroptosis has been implicated in the occurrence and treatment response of various types of cancer, and targeting ferroptosis has emerged as a promising strategy for cancer therapy. However, cancer cells can escape cellular ferroptosis by activating or remodeling various signaling pathways, including oxidative stress pathways, thereby limiting the efficacy of ferroptosis-activating targeted therapy. The key anti-oxidative transcription factor, nuclear factor E2 related factor 2 (Nrf2 or NFE2L2), plays a dominant role in defense machinery by reprogramming the iron, intermediate, and glutathione peroxidase 4 (GPX4)-related network and the antioxidant system to attenuate ferroptosis. In this review, we summarize the recent advances in the regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy and explore the prospect of combining Nrf2 inhibitors and ferroptosis inducers as a promising cancer treatment strategy.
    Keywords:  antioxidant system; cancer therapy; drug resistance; ferroptosis; iron metabolism; nuclear factor E2 related factor 2 (Nrf2)
    DOI:  https://doi.org/10.1038/s41401-024-01336-2
  5. Toxicol In Vitro. 2024 Jul 17. pii: S0887-2333(24)00131-0. [Epub ahead of print] 105901
    Nrf2 affects DNA damage repair and cell apoptosis through regulating HR and the intrinsic Caspase-dependent apoptosis pathway in TK6 cells exposed to hydroquinone.
    Lin Chen, Pu Guo, Lu Zhai, Lingxue Yu, Delong Zhu, Xiaoyi Hu, Zhuanzhuan Li, Yuting Chen, Qian Sun, Lei Sun, Hao Luo, Huanwen Tang.
      Hydroquinone (HQ) is one of benzene metabolites that can cause oxidative stress damage and Homologous recombination repair (HR). A good deal of reactive oxygen species (ROS) generated by oxidative stress can trigger apoptotic signaling pathways. The nuclear factor erythroid 2-related factor 2 (Nrf2) can regulate the cell response to oxidative stress damage. The aim of this study was to explore whether Nrf2 participate in HQ-induced apoptosis and its mechanism. The findings displayed that HQ triggered HR, promoted Nrf2 transfer into the cell nucleus and induced cell apoptosis, while Nrf2 deficient elevated cell apoptosis, attenuated the expression of PARP1 and RAD51. We also observed that Nrf2 deficient triggered Caspase-9. Thus, we speculated that Nrf2 might participate in HQ-induced cell apoptosis through Caspase-9 dependent pathways. Meanwhile, Nrf2 participated in HQ-induced DNA damage repair by regulating the level of PARP1 and RAD51.
    Keywords:  Caspase-9; Cell apoptosis; Hydroquinone; Nrf2; P53
    DOI:  https://doi.org/10.1016/j.tiv.2024.105901
  6. Am J Cancer Res. 2024 ;14(6): 2790-2804
    Citraconate promotes the malignant progression of colorectal cancer by inhibiting ferroptosis.
    Zongjiong Mai, Yanyu Li, Lei Zhang, Hongyu Zhang.
      Metastasis is a principal factor in the poor prognosis of colorectal cancer. Recent studies have found microbial metabolites regulate colorectal cancer metastasis. By analyzing metabolomics data, we identified an essential fecal metabolite citraconate that potentially promotes colorectal cancer metastasis. Next, we tried to reveal its effect on colorectal cancer and the underlying mechanism. Firstly, the response of colorectal cancer cells (HCT116 and MC38 cells) to citraconate was assessed by Cell Counting Kit-8 assay, clonogenic assay, transwell migration and invasion assay. Moreover, we utilized an intra-splenic injection model to evaluate the effect of citraconate on colorectal cancer liver metastasis in vivo. Then molecular approaches were employed, including RNA sequencing, mass spectrometry-based metabolomics, western blot, quantitative real-time PCR, cell ferrous iron colorimetric assay and intracellular malondialdehyde measurement. In vitro, citraconate promotes the growth of colorectal cancer cells. In vivo, citraconate aggravated liver metastasis of colorectal cancer. Mechanistically, downstream genes of NRF2, NQO1, GCLC, and GCLM high expression induced by citraconate resulted in resistance to ferroptosis of colorectal cancer cells. In summary, citraconate promotes the malignant progression of colorectal cancer through NRF2-mediated ferroptosis resistance in colorectal cancer cells. Furthermore, our study indicates that fecal metabolite may be crucial in colorectal cancer development.
    Keywords:  Citraconate; colorectal cancer; ferroptosis; malignant progression
    DOI:  https://doi.org/10.62347/LWRS3363
  7. Cureus. 2024 Jul;16(7): e64849
    Ethnic Differences, Lung Cancer Risk, and Association of NRF2 Gene Polymorphism with Gemcitabine-Based Chemotherapy.
    Tirumalasetty Devika, Ganesapandian Mahalakshmi, K Mythili, Katiboina Srinivasa Rao, Suresh Kumar Srinivasamurthy, Dubashi Biswajit, Deepak Gopal Shewade.
       INTRODUCTION: The cancer burden is rising every year. Lung cancer is one of the most common cancers and non-small cell lung cancer is the most common type. Chemotherapy based on platinum drugs and third-generation nucleoside anti-metabolites such as gemcitabine are used widely. Gemcitabine has a complex metabolic pathway, with many mechanisms contributing to its cytotoxicity. Derangements in the metabolic pathway genes contribute to drug resistance and toxicity with this drug. Association studies including these genetic polymorphisms in the metabolic pathway, clinical outcomes, and cancer risk reported inter-individual differences. Thus, the aim of this study was to ascertain the role of these genetic variants in South Indian cancer patients treated with gemcitabine-based therapy.
    METHODS: The study was done with 184 healthy volunteers for frequency establishment and 123 cancer patients were treated with gemcitabine-based chemotherapy for response and toxicity assessment. The participants were aged 18-65 years and resided in the southern states of India. DNA extraction was done from the leukocyte fraction of the blood by phenol-chloroform extraction procedures and genotyping was done by reverse transcription-polymerase chain reaction (RT-PCR) techniques to identify DNA repair gene polymorphisms. Tumor response was determined using Response evaluation criteria in solid tumors (RECIST) guidelines and toxicity using Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. The patients were followed up for survival analysis.
    RESULTS: The minor allele frequency of the single nucleotide polymorphism (SNP) NRF2-617 C>A (rs6721961) in the healthy population was 12.8%. SNPs were in Hardy-Weinberg equilibrium (p>0.05). Gender-based differences were not observed with the studied SNP in the healthy population and the lung cancer patients. These frequencies of NRF2 were found to be similar when compared to EUR (European) and all the South Asian subpopulations. They are significantly divergent compared to AFR (African), AMR (American), and EAS (East Asian) populations. The minor allele frequency in cancer patients was found to be 14.2% and the lung cancer risk with the SNP studied could not be detected. There was no association found with the response, toxicity, and survival among lung cancer patients.
    CONCLUSION: NRF2, being a multifaced molecule, did not show a significant association with lung cancer risk, response, and toxicity in patients with gemcitabine-based chemotherapy.
    Keywords:  chemotherapy; gemcitabine; lung cancer; nrf2; polymorphisms; rs6721961 c>a; south indians
    DOI:  https://doi.org/10.7759/cureus.64849
  8. J Cancer. 2024 ;15(14): 4577-4590
    EGR1 Promotes Erastin-induced Ferroptosis Through Activating Nrf2-HMOX1 Signaling Pathway in Breast Cancer Cells.
    Zhirong Lin, Zifei Liu, Zhilong Pan, Yunyi Zhang, Xinyu Yang, Yaxin Feng, Ruihua Zhang, Wenfeng Zeng, Chang Gong, Jianing Chen.
      Purpose: Early growth response 1 (EGR1) is a crucial transcription factor composed of zinc finger structures, inhibitory and activating regulatory regions. We identified the biological effect and molecular mechanisms of EGR1 in breast cancer (BC). Methods: We used qRT-PCR, western blot and immunohistochemistry to examine the expression of EGR1 in BC samples. CCK-8 and colony assay were performed to reveal the effect of EGR1 on the proliferation of BC cells. LDH release assay, MCB assay, MDA assay, C-AM assay and TMRE assay were performed to measure the levels of LDH release, GSH, MDA, LIP and mitochondrial membrane potential. The regulation of EGR1 on the expression of Nrf2 and HMOX1 was investigated through Western blot. Xenograft models were conducted to determine the impact of EGR1 overexpression on BC in vivo. Results: The expression of EGR1 was downregulated in BC tissues compared with the normal tissues, and lower expression of EGR1 associated with poorer clinical outcome in BC patients. Through in vitro experiments, we found that EGR1 downregulation facilitated the proliferation of BC cells, and overexpression of EGR1 inhibited the proliferation of BC cells. In addition, EGR1 knockdown alleviated erastin-induced ferroptosis and overexpression of EGR1 facilitated erastin-induced ferroptosis in BC cells. Moreover, overexpression of EGR1 facilitated the anti-tumor effect caused by erastin in vivo. Mechanistically, the phosphorylation levels of Nrf2 and the expression of HMOX1 were reduced due to the downregulation of EGR1, and increased due to the upregulation of EGR1. Additionally, the finding that EGR1 facilitated erastin-induced ferroptosis was alleviated by the inhibition of Nrf2-HMOX1. Conclusion: The expression of EGR1 is downregulated in BC, which is correlated with poor prognosis of BC patients. EGR1 suppresses the proliferation of BC cells and facilitates erastin-induced ferroptosis by activating Nrf2-HMOX1 signaling pathway in BC cells.
    Keywords:  EGR1; breast cancer; ferroptosis; prognosis.
    DOI:  https://doi.org/10.7150/jca.95328
  9. iScience. 2024 Jul 19. 27(7): 110137
    Excess endocrine growth hormone in acromegaly promotes the aggressiveness and metastasis of triple-negative breast cancer.
    Chan Woo Kang, Ju Hun Oh, Eun Kyung Wang, Yaru Bao, Ye Bin Kim, Min-Ho Lee, Yang Jong Lee, Young Seok Jo, Cheol Ryong Ku, Eun Jig Lee.
      Pituitary adenoma-induced excess endocrine growth hormone (GH) secretion can lead to breast cancer development and metastasis. Herein, we used an acromegaly mouse model to investigate the role of excess endocrine GH on triple-negative breast cancer (TNBC) growth and metastasis. Additionally, we aimed to elucidate the molecular mechanism of transcription factor 20 (TCF20)/nuclear factor erythroid 2-related factor 2 (NRF2) signaling-mediated aggressiveness and metastasis of TNBC. Excess endocrine GH induced TCF20 activates the transcription of NRF2 and NRF2-target genes to facilitate TNBC metastasis. Inhibition of GH receptor (GHR) and TCF20 activity using the GHR antagonist or small-interfering RNA-induced gene knockdown resulted in reduced tumor volume and metastasis, suggesting that excess endocrine GH stimulates TCF20/NRF2 pathways in TNBC and promotes metastasis to the lung. GHR inhibitors present an effective therapeutic strategy to prevent TNBC cell growth and metastasis. Our findings revealed functional and mechanistic roles of the GH-TCF20-NRF2 signaling axis in TBNC progression.
    Keywords:  endocrine regulation; natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.110137
  10. Funct Integr Genomics. 2024 Jul 16. 24(4): 126
    A novel antitumor mechanism of triptonide in colorectal cancer: inducing ferroptosis via the SLC7A11/GPX4 axis.
    Weijie Wang, Xiaofen Zhao, Jie Zhou, Hai Li.
      Colorectal cancer (CRC) is a prevalent malignancy affecting the human digestive tract. Triptonide has been shown to have some anticancer activity, but its effect in CRC is vague. Herein, we examined the effect of triptonide on CRC. In this study, the results of bioinformatics analysis displayed that triptonide may regulate ferroptosis in CRC by modulating GPX4 and SLC7A11. In HCT116 and LoVo cells, the expression levels of GPX4 and SLC7A11 were significantly reduced after triptonide management versus the control group. Triptonide inhibited proliferation, but promoted ferroptosis in CRC cells. SLC7A11 upregulation overturned the effects of triptonide on proliferation and ferroptosis in CRC cells. Triptonide inhibited activation of the PI3K/AKT/Nrf2 signaling in CRC cells. Activation of the PI3K/AKT signaling or Nrf2 upregulation overturned the effects of triptonide on proliferation and ferroptosis in CRC cells. Triptonide suppressed CRC cell growth in vivo by modulating SLC7A11 and GPX4. In conclusion, Triptonide repressed proliferation and facilitated ferroptosis of CRC cells by repressing the SLC7A11/GPX4 axis through inactivation of the PI3K/AKT/Nrf2 signaling.
    Keywords:  Colorectal cancer; Ferroptosis; PI3K/AKT/Nrf2 signaling; Proliferation; Triptonide
    DOI:  https://doi.org/10.1007/s10142-024-01402-2
  11. J Inorg Biochem. 2024 Jul 14. pii: S0162-0134(24)00190-9. [Epub ahead of print]259 112666
    Three Ru(II) complexes modulate the antioxidant transcription factor Nrf2 to overcome cisplatin resistance.
    Lanmei Chen, Hong Tang, Tianling Hu, Jie Wang, Qianqian Ouyang, Xufeng Zhu, Rui Wang, Wenyong Huang, Zunnan Huang, Jincan Chen.
      Here, we designed, synthesized and characterized three new cyclometalated Ru(II) complexes, [Ru(phen)2(1-(4-Ph-Ph)-IQ)]+ (phen = 1,10-phenanthroline, IQ = isoquinoline, RuIQ9), [Ru(phen)2(1-(4-Ph-Ph)-7-OCH3-IQ)]+ (RuIQ10), and [Ru(phen)2(1-(4-Ph-Ph)-6,7-(OCH3)2-IQ)]+ (RuIQ11). The cytotoxicity experiments conducted on both 2D and 3D multicellular tumor spheroids (MCTSs) indicated that complexes RuIQ9-11 exhibited notably higher cytotoxicity against A549 and A549/DDP cells when compared to the ligands and precursor compounds as well as clinical cisplatin. Moreover, the Ru(II) complexes displayed low toxicity when tested on normal HBE cells in vitro and exposed to zebrafish embryos in vivo. In addition, complexes RuIQ9-11 could inhibit A549 and A549/DDP cell migration and proliferation by causing cell cycle arrest, mitochondrial dysfunction, and elevating ROS levels to induce apoptosis in these cells. Mechanistic studies revealed that RuIQ9-11 could suppress the expression of Nrf2 and its downstream antioxidant protein HO-1 by inhibiting Nrf2 gene transcription in drug-resistant A549/DDP cells. Simultaneously, they inhibited the expression of efflux proteins MRP1 and p-gp in drug-resistant cells, ensuring the accumulation of the complexes within the cells. This led to an increase in intracellular ROS levels in drug-resistant cells, ultimately causing damage and cell death, thus overcoming cisplatin resistance. More importantly, RuIQ11 could effectively inhibit the migration and proliferation of drug-resistant cells within zebrafish, addressing the issue of cisplatin resistance. Accordingly, the prepared Ru(II) complexes possess significant potential for development as highly effective and low-toxicity lung cancer therapeutic agents to overcome cisplatin resistance.
    Keywords:  3D MCTs; Cisplatin resistance; Nrf2; Ru(II) complexes; Zebrafish model
    DOI:  https://doi.org/10.1016/j.jinorgbio.2024.112666
  12. Scand J Immunol. 2023 Dec;98(6): e13322
    Sphingosine 1-phosphate combining with S1PR4 promotes regulatory T cell differentiation related to FAO through Nrf2/PPARα.
    Rui Feng, Chuang Liu, Zilin Cui, Zirong Liu, Yamin Zhang.
      Metabolism and metabolic processes have long been considered to shape the tumour immunosuppressive microenvironment. Recent research has demonstrated that T regulatory cells (Tregs) display high rates of fatty acid oxidation (FAO) and a relatively low rate of glycolysis. Sphingosine 1-phosphate (S1P), which is a G protein signalling activator involved in immune regulation and FAO modulation, has been implicated in Treg differentiation. However, the precise relation between Treg differentiation and S1P remains unclear. In this study, we isolated naïve CD4+ T cells from the spleens of 6-8-week-old BALB/c mice using magnetic bead sorting, which was used in our study for Treg differentiation. S1P stimulation was performed during Treg differentiation. We examined the oxygen consumption and palmitic acid metabolism of the differentiated Tregs and evaluated the expression levels of various proteins, including Nrf2, CPT1A, Glut1, ACC1 and PPARα, through Western blotting. Our results demonstrate that S1P promotes Treg differentiation and enhances FAO, and that the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor α (PPARα) is upregulated. Furthermore, Nrf2 or PPARα knockdown dampened the Treg differentiation and FAO that were promoted by S1P, confirming that S1P can bind with S1PR4 to promote Treg differentiation through the Nrf2/PPARα signalling pathway, which may be related to FAO facilitation.
    Keywords:  differentiation; fatty acid oxidation; nuclear factor (erythroid‐derived 2)‐like 2; regulatory T cell; sphingosine 1‐phosphate
    DOI:  https://doi.org/10.1111/sji.13322
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