bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023‒07‒30
eleven papers selected by
Caner Geyik
Istinye University
  1. The mechanistic insights of the antioxidant Keap1-Nrf2 pathway in oncogenesis: a deadly scenario.
  2. Retracted: lncRNA GAS5 Induces Cell Apoptosis in Acute Myeloid Leukemia by Targeting Nrf2.
  3. Roles of Oxidative Stress and Nrf2 Signaling in Pathogenic and Non-Pathogenic Cells: A Possible General Mechanism of Resistance to Therapy.
  4. NRF2: New Mechanistic Insights and Therapeutic Perspectives.
  5. NRF2 participates in the suppressive tumor immune microenvironment of KRAS/KEAP1 co-mutant non-small cell lung cancer by inhibiting the STING pathway.
  6. NFE2L2 and STAT3 Converge on Common Targets to Promote Survival of Primary Lymphoma Cells.
  7. B7-H3 confers stemness characteristics to gastric cancer cells by promoting glutathione metabolism through AKT/pAKT/Nrf2 pathway.
  8. Phloretin-induced STAT3 inhibition suppresses pancreatic cancer growth and progression via enhancing Nrf2 activity.
  9. Exploring ACSL4/LPCAT3/ALOX15 and SLC7A11/GPX4/NFE2L2 as potential targets in ferroptosis-based cancer therapy.
  10. Nrf2: a dark horse in doxorubicin-induced cardiotoxicity.
  11. Ammonium tetrathiomolybdate relieves oxidative stress in cisplatin-induced acute kidney injury via NRF2 signaling pathway.
  1. Med Oncol. 2023 Jul 22. 40(9): 248
    The mechanistic insights of the antioxidant Keap1-Nrf2 pathway in oncogenesis: a deadly scenario.
    Anirban Goutam Mukherjee, Abilash Valsala Gopalakrishnan.
      The Nuclear factor erythroid 2-related factor 2 (Nrf2) protein has garnered significant interest due to its crucial function in safeguarding cells and tissues. The Nrf2 protein is crucial in preserving tissue integrity by safeguarding cells against metabolic, xenobiotic and oxidative stress. Due to its various functions, Nrf2 is a potential pharmacological target for reducing the incidence of diseases such as cancer. However, mutations in Keap1-Nrf2 are not consistently favored in all types of cancer. Instead, they seem to interact with specific driver mutations of tumors and their respective tissue origins. The Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway mutations are a powerful cancer adaptation that utilizes inherent cytoprotective pathways, encompassing nutrient metabolism and ROS regulation. The augmentation of Nrf2 activity elicits significant alterations in the characteristics of neoplastic cells, such as resistance to radiotherapy and chemotherapy, safeguarding against apoptosis, heightened invasiveness, hindered senescence, impaired autophagy and increased angiogenesis. The altered activity of Nrf2 can arise from diverse genetic and epigenetic modifications that instantly impact Nrf2 regulation. The present study aims to showcase the correlation between the Keap1-Nrf2 pathway and the progression of cancers, emphasizing genetic mutations, metabolic processes, immune regulation, and potential therapeutic strategies. This article delves into the intricacies of Nrf2 pathway anomalies in cancer, the potential ramifications of uncontrolled Nrf2 activity, and therapeutic interventions to modulate the Keap1-Nrf2 pathway.
    Keywords:  Cancer; Cytoprotection; Keap 1; Nrf2; Oncogene; ROS
    DOI:  https://doi.org/10.1007/s12032-023-02124-4
  2. Dis Markers. 2023 ;2023 9808761
    Retracted: lncRNA GAS5 Induces Cell Apoptosis in Acute Myeloid Leukemia by Targeting Nrf2.
    Disease Markers.
      [This retracts the article DOI: 10.1155/2022/5178122.].
    DOI:  https://doi.org/10.1155/2023/9808761
  3. Antioxidants (Basel). 2023 Jun 30. pii: 1371. [Epub ahead of print]12(7):
    Roles of Oxidative Stress and Nrf2 Signaling in Pathogenic and Non-Pathogenic Cells: A Possible General Mechanism of Resistance to Therapy.
    Mira Hammad, Mohammad Raftari, Rute Cesário, Rima Salma, Paulo Godoy, S Noushin Emami, Siamak Haghdoost.
      The coordinating role of nuclear factor erythroid-2-related factor 2 (Nrf2) in cellular function is undeniable. Evidence indicates that this transcription factor exerts massive regulatory functions in multiple signaling pathways concerning redox homeostasis and xenobiotics, macromolecules, and iron metabolism. Being the master regulator of antioxidant system, Nrf2 controls cellular fate, influencing cell proliferation, differentiation, apoptosis, resistance to therapy, and senescence processes, as well as infection disease success. Because Nrf2 is the key coordinator of cell defence mechanisms, dysregulation of its signaling has been associated with carcinogenic phenomena and infectious and age-related diseases. Deregulation of this cytoprotective system may also interfere with immune response. Oxidative burst, one of the main microbicidal mechanisms, could be impaired during the initial phagocytosis of pathogens, which could lead to the successful establishment of infection and promote susceptibility to infectious diseases. There is still a knowledge gap to fill regarding the molecular mechanisms by which Nrf2 orchestrates such complex networks involving multiple pathways. This review describes the role of Nrf2 in non-pathogenic and pathogenic cells.
    Keywords:  ROS: Nrf2 signaling; adipogenesis; cancer; cancer stem cell; infection diseases; malaria; osteogenesis; oxidative stress; stem cell differentiation; treatment resistance
    DOI:  https://doi.org/10.3390/antiox12071371
  4. Antioxid Redox Signal. 2023 Jul 28.
    NRF2: New Mechanistic Insights and Therapeutic Perspectives.
    Jerzy W Kupiec-Weglinski.
      Targeted modulation of a dynamic interplay between transcription factor NRF2 and its negative regulator, KEAP1, is of paramount importance in maintaining redox, metabolic, and protein homeostasis and regulating inflammation responses. Indeed, inducible NRF2 activation promotes cytoprotective mechanisms against many immune, neurodegenerative and metabolic disorders with oxidative stress and inflammation as underlying pathological features. In this ARS Forum issue, five state-of-the-art reviews and two original research communications report on canonical and newly discovered molecular mechanisms by which the NRF2 - KEAP1 axis controls fundamental cell life or death decisions and exerts biological functions under environmental and endogenous stress conditions. Although the use of NRF2 activators represents a promising pharmacological strategy to regain and maintain homeostasis, challenges regarding their double-edged character, target specificity, pharmacodynamic properties, efficacy, and safety must be critically considered. More translational studies are warranted before NRF2 agonists (inducers or enhancers) become an integral part of our therapeutic armamentarium.
    DOI:  https://doi.org/10.1089/ars.2023.0398
  5. Genes Dis. 2023 Sep;10(5): 1727-1730
    NRF2 participates in the suppressive tumor immune microenvironment of KRAS/KEAP1 co-mutant non-small cell lung cancer by inhibiting the STING pathway.
    Sun Xiaodan, Zhao Peiyan, Li Hui, Liu Yan, Cheng Ying.
      
    DOI:  https://doi.org/10.1016/j.gendis.2022.10.009
  6. Int J Mol Sci. 2023 Jul 18. pii: 11598. [Epub ahead of print]24(14):
    NFE2L2 and STAT3 Converge on Common Targets to Promote Survival of Primary Lymphoma Cells.
    Andrea Arena, Michele Di Crosta, Roberta Gonnella, Roberta Zarrella, Maria Anele Romeo, Rossella Benedetti, Maria Saveria Gilardini Montani, Roberta Santarelli, Gabriella D'Orazi, Mara Cirone.
      NFE2L2 and STAT3 are key pro-survival molecules, and thus, their targeting may represent a promising anti-cancer strategy. In this study, we found that a positive feedback loop occurred between them and provided evidence that their concomitant inhibition efficiently impaired the survival of PEL cells, a rare, aggressive B cell lymphoma associated with the gammaherpesvirus KSHV and often also EBV. At the molecular level, we found that NFE2L2 and STAT3 converged in the regulation of several pro-survival molecules and in the activation of processes essential for the adaption of lymphoma cells to stress. Among those, STAT3 and NFE2L2 promoted the activation of pathways such as MAPK3/1 and MTOR that positively regulate protein synthesis, sustained the antioxidant response, expression of molecules such as MYC, BIRC5, CCND1, and HSP, and allowed DDR execution. The findings of this study suggest that the concomitant inhibition of NFE2L2 and STAT3 may be considered a therapeutic option for the treatment of this lymphoma that poorly responds to chemotherapies.
    Keywords:  DDR; HSPs; NRF2; PEL; STAT3; autophagy; c-Myc; p62/SQSTM1
    DOI:  https://doi.org/10.3390/ijms241411598
  7. Chin Med J (Engl). 2023 Jul 24.
    B7-H3 confers stemness characteristics to gastric cancer cells by promoting glutathione metabolism through AKT/pAKT/Nrf2 pathway.
    Lu Xia, Yuqi Chen, Juntao Li, Jiayu Wang, Kanger Shen, Anjing Zhao, Haiyan Jin, Guangbo Zhang, Qinhua Xi, Suhua Xia, Tongguo Shi, Rui Li.
      BACKGROUND: Cancer stem-like cells (CSCs) are a small subset of cells in tumors that exhibit self-renewal and differentiation properties. CSCs play a vital role in tumor formation, progression, relapse, and therapeutic resistance. B7-H3, an immunoregulatory protein, has many protumor functions. However, little is known about the mechanism underlying the role of B7-H3 in regulating gastric cancer (GC) stemness. Our study aimed to explore the impacts of B7-H3 on GC stemness and its underlying mechanism.METHODS: GC stemness influenced by B7-H3 was detected both in vitro and in vivo. The expression of stemness-related markers was examined by reverse transcriptase quantitative polymerase chain reaction, Western blotting, and flow cytometry. Sphere formation assay was used to detect the sphere-forming ability. The underlying regulatory mechanism of B7-H3 on the stemness of GC was investigated by mass spectrometry and subsequent validation experiments. The signaling pathway (Protein kinase B [Akt]/Nuclear factor erythroid 2-related factor 2 [Nrf2] pathway pathway) of B7-H3 on the regulation of glutathione (GSH) metabolism was examined by Western blotting assay. Multi-color Immunohistochemistry (mIHC) was used to detect the expression of B7-H3, cluster of differentiation 44 (CD44), and Nrf2 on human GC tissues. Student's t-test was used to compare the difference between two groups. Pearson correlation analysis was used to analyze the relationship between two molecules. The Kaplan-Meier method was used for survival analysis.
    RESULTS: B7-H3 knockdown suppressed the stemness of GC cells both in vitro and in vivo. Mass spectrometric analysis showed the downregulation of GSH metabolism in short hairpin B7-H3 GC cells, which was further confirmed by the experimental results. Meanwhile, stemness characteristics in B7-H3 overexpressing cells were suppressed after the inhibition of glutathione (GSH) metabolism. Furthermore, Western blotting suggested that B7-H3-induced activation of GSH metabolism occurred through the AKT/Nrf2 pathway, and inhibition of AKT signaling pathway could suppress not only GSH metabolism but also GC stemness. mIHC showed that B7-H3 was highly expressed in GC tissues and was positively correlated with the expression of CD44 and Nrf2. Importantly, GC patients with high expression of B7-H3, CD44, and Nrf2 had worse prognosis (P = 0.02).
    CONCLUSIONS: B7-H3 has a regulatory effect on GC stemness and the regulatory effect is achieved through the AKT/Nrf2/GSH pathway. Inhibiting B7-H3 expression may be a new therapeutic strategy against GC.
    DOI:  https://doi.org/10.1097/CM9.0000000000002772
  8. Phytomedicine. 2023 Jul 20. pii: S0944-7113(23)00351-3. [Epub ahead of print]118 154990
    Phloretin-induced STAT3 inhibition suppresses pancreatic cancer growth and progression via enhancing Nrf2 activity.
    Qingqing Ruan, Chunmei Wen, Guihua Jin, Ziwei Yuan, Xuejia Yang, Zhikai Wen, Gang Huang, Guogang Li, Jie Deng, Yongheng Bai.
      BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic tumor charactered by a rapid progression and high lethal rate. Hyperactivation of STAT3 signaling exerts a vital effect on the growth and progression of PDAC. While dietary flavonoid phloretin has anti-inflammatory and antioxidant activities, it remains unclear whether phloretin has anti-tumor effects on PDAC.PURPOSE: The focus of the present study is to elucidate the effects of phloretin on PDAC and investigate its underlying molecular mechanisms.
    STUDY DESIGN AND METHODS: Effect of phloretin were assessed in the pancreatic cancer cells (PCCs) by colony formation assay, real-time cell analysis, flow cytometry, Immunofluorescence staining, and cell migration assay. The expressions of mRNA and protein were respectively analyzed by quantitative PCR and Western blotting. A xenograft model was used to appraise the antitumor efficacy of phloretin.
    RESULTS: Phloretin treatment significantly restrained cell viability and metastasis, induced DNA injury and ROS accumulation, and triggered mitochondrial-dependent apoptosis in PCCs. Mechanistically, phloretin exhibits anti-tumor potential via inactivating STAT3 signaling and enhancing Nrf2 activity. STAT3 overexpression and Nrf2 silencing partially relieved phloretin-induced inhibition on cell growth and metastasis in PCCs. Phloretin remarkably blocked pancreatic tumor growth and metastasis in vivo.
    CONCLUSIONS: Phloretin suppresses pancreatic cancer growth and progression through inhibition of STAT3 mediated by enhancing Nrf2 activity. Phloretin may serve as a promising therapeutic agent for PDAC.
    Keywords:  Apoptosis; Epithelial-mesenchymal transition; Nrf2; Pancreatic ductal adenocarcinoma; Phloretin; STAT3
    DOI:  https://doi.org/10.1016/j.phymed.2023.154990
  9. Future Med Chem. 2023 Jul 28.
    Exploring ACSL4/LPCAT3/ALOX15 and SLC7A11/GPX4/NFE2L2 as potential targets in ferroptosis-based cancer therapy.
    Gaurav Gupta, Asif Ahmad Bhat, Ahsas Goyal, Neelam Singla, Saurabh Gupta, Sanjay Sharma, Shvetank Bhatt, Kamal Dua.
      
    Keywords:  antioxidants; cancer; drug therapy; ferroptosis; reactive oxygen species
    DOI:  https://doi.org/10.4155/fmc-2023-0125
  10. Cell Death Discov. 2023 Jul 26. 9(1): 261
    Nrf2: a dark horse in doxorubicin-induced cardiotoxicity.
    Xiaopeng Zhao, Zheng Tian, Mingli Sun, Dan Dong.
      Being a broad-spectrum anticancer drug, doxorubicin is indispensable for clinical treatment. Unexpectedly, its cardiotoxic side effects have proven to be a formidable obstacle. Numerous studies are currently devoted to elucidating the pathological mechanisms underlying doxorubicin-induced cardiotoxicity. Nrf2 has always played a crucial role in oxidative stress, but numerous studies have demonstrated that it also plays a vital part in pathological mechanisms like cell death and inflammation. Numerous studies on the pathological mechanisms associated with doxorubicin-induced cardiotoxicity demonstrate this. Several clinical drugs, natural and synthetic compounds, as well as small molecule RNAs have been demonstrated to prevent doxorubicin-induced cardiotoxicity by activating Nrf2. Consequently, this study emphasizes the introduction of Nrf2, discusses the role of Nrf2 in doxorubicin-induced cardiotoxicity, and concludes with a summary of the therapeutic modalities targeting Nrf2 to ameliorate doxorubicin-induced cardiotoxicity, highlighting the potential value of Nrf2 in doxorubicin-induced cardiotoxicity.
    DOI:  https://doi.org/10.1038/s41420-023-01565-0
  11. Cell Death Discov. 2023 Jul 25. 9(1): 259
    Ammonium tetrathiomolybdate relieves oxidative stress in cisplatin-induced acute kidney injury via NRF2 signaling pathway.
    Hao Qi, Haoyu Shi, Minbo Yan, Liangyu Zhao, Yinghao Yin, Xiaolin Tan, Huiyue Qi, Hu Li, Kangqiang Weng, Yuxin Tang, Yingbo Dai.
      Cisplatin is an efficient chemotherapeutic agent for various solid tumors, but its usage is restricted by nephrotoxicity. A single dose of cisplatin can cause acute kidney injury (AKI), which is characterized by rapid reduction in kidney function. However, the current therapies, such as hydration, are limited. It is vital to develop novel therapeutic reagents that have both anticancer and renoprotective properties. The objective of this study was to determine whether ammonium tetrathiomolybdate (TM), a copper chelator used to treat cancer and disorders of copper metabolism, may offer protection against cisplatin-induced AKI. In this study, we demonstrated that TM treatment had antioxidative effects and mitigated cisplatin-induced AKI both in vivo and in vitro. Mechanically, TM inhibited NRF2 ubiquitination, which activated the NRF2 pathway in HK-2 cells and promoted the expression of target genes. It should be noted that the protective effect conferred by TM against cisplatin was compromised by the knockdown of the NRF2 gene. Furthermore, TM selectively activated the NRF2 pathways in the liver and kidney. The current study provided evidence for additional clinical applications of TM by showing that it activates NRF2 and has a favorable therapeutic impact on cisplatin-induced AKI.
    DOI:  https://doi.org/10.1038/s41420-023-01564-1
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