bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023–12–17
eleven papers selected by
Caner Geyik, Istinye University
  1. Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2.
  2. Inhibition of ferroptosis by POLE2 in gastric cancer cells involves the activation of NRF2/GPX4 pathway.
  3. Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance.
  4. Syringic acid alleviates cisplatin-induced ovarian injury through modulating endoplasmic reticulum stress, inflammation and Nrf2 pathway.
  5. Cepharanthine, a regulator of keap1-Nrf2, inhibits gastric cancer growth through oxidative stress and energy metabolism pathway.
  6. Live-cell imaging Unveils stimulus-specific dynamics of Nrf2 activation in UV-exposed melanoma cells: Implications for antioxidant compound screening.
  7. Bardoxolone methyl attenuates doxorubicin-induced cardiotoxicity by inhibiting the TXNIP-NLRP3 pathway through Nrf2 activation.
  8. Alpha-Lipoic Acid Reduces Cell Growth, Inhibits Autophagy, and Counteracts Prostate Cancer Cell Migration and Invasion: Evidence from In Vitro Studies.
  9. Glutaminase inhibition as potential cancer therapeutics: current status and future applications.
  10. Retracted: A2/B1 Promotes NRF2 mRNA Stability and Inhibits Ferroptosis and Cell Proliferation in Breast Cancer Cells.
  11. Retracted: Nestin Regulates Keap1-Nrf2-HO-1-Mediated Antioxidant Responses during Stress and Malignant Hematopoiesis.
  1. J Endocrinol Invest. 2023 Dec 07.
    Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2.
    Z Gong, L Xue, A C Vlantis, C A van Hasselt, J Y K Chan, J Fang, R Wang, Y Yang, D Li, X Zeng, M C F Tong, G G Chen.
       BACKGROUND: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) can be developed from differentiated thyroid cancer, and this dedifferentiated transformation leads to poor prognosis and high mortality. The role of Nrf2 in the dedifferentiation of differentiated thyroid cancer (DTC) induced by KRAS remains unclear.
    METHODS AND MATERIALS: In this study, two DTC cell lines, BCPAP and WRO, were used to evaluate the function of Nrf2 in the dedifferentiation caused by wild-type KRAS (KRAS-WT) and G12V point mutation KRAS (KRAS-G12V).
    RESULTS: The overexpression of KRAS-WT and KRAS-G12V increased the proliferative and invasive ability of BCPAP and WRO cells. Aggressive morphology was observed in KRAS-WT and KRAS-G12V overexpressed WRO cells. These results suggested that overexpression of KRAS-WT or KRAS-G12V may induce dedifferentiation in DTC cells. The expression of Nrf2 was increased by KRAS-WT and KRAS-G12V in DTC cells. In addition, compared with normal thyroid tissues, the expression of Nrf2 protein was considerably higher in thyroid cancer tissues on immunohistochemistry (IHC) staining, and the increased expression of Nrf2 indicated a poor prognosis of thyroid cancer. These results indicated that Nrf2 is the KRAS downstream molecule in thyroid cancer. Functional studies showed that the Nrf2 inhibitor Brusatol counteracted the proliferative and invasive abilities induced by KRAS-WT and KRAS-G12V in BCPAP and WRO cells. In addition, the xenograft assay further confirmed that Brusatol inhibits tumor growth induced by KRAS-WT and KRAS-G12V.
    CONCLUSION: Collectively, this study suggests that Nrf2 could be a promising therapeutic target in KRAS-mediated dedifferentiation of thyroid cancer.
    Keywords:  Brusatol; Dedifferentiation; KRAS; Nrf2; Thyroid cancer
    DOI:  https://doi.org/10.1007/s40618-023-02248-4
  2. J Cell Mol Med. 2023 Dec 09.
    Inhibition of ferroptosis by POLE2 in gastric cancer cells involves the activation of NRF2/GPX4 pathway.
    Hui Jian, Zhi-Qiang Chen, Heng Du, Ting Liao, Yi-Chen Sun, Dong Ke, Yang Yu.
      Gastric cancer results in great cancer mortality worldwide, and inducing ferroptosis dramatically improves the malignant phenotypes of gastric cancer. DNA polymerase epsilon subunit 2 (POLE2) plays indispensable roles in tumorigenesis; however, its involvement and molecular basis in ferroptosis and gastric cancer are not clear. Human gastric cancer cells were infected with lentiviral vectors to knock down or overexpress POLE2, and cell ferroptosis was detected. To further validate the involvement of nuclear factor erythroid 2-related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4), lentiviral vectors were used. POLE2 expression was elevated in human gastric cancer cells and tissues and closely correlated with clinicopathological features in gastric cancer patients. POLE2 knockdown was induced, while POLE2 overexpression inhibited ferroptosis of human gastric cancer cells, thereby modulating the malignant phenotypes of gastric cancer. Mechanistic studies revealed that POLE2 overexpression elevated NRF2 expression and activity and subsequently activated GPX4, which then prevented lipid peroxidation and ferroptosis in human gastric cancer cells. In contrast, either NRF2 or GPX4 silence significantly prevented POLE2 overexpression-mediated inductions of cell proliferation, migration, invasion and inhibition of ferroptosis. POLE2 overexpression inhibits ferroptosis in human gastric cancer cells through activating NRF2/GPX4 pathway, and inhibiting POLE2 may be a crucial strategy to treat gastric cancer.
    Keywords:  GPX4; POLE2; ferroptosis; gastric cancer
    DOI:  https://doi.org/10.1111/jcmm.17983
  3. J Clin Invest. 2023 Dec 07. pii: e174528. [Epub ahead of print]
    Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance.
    Dominik J Schaer, Nadja Schulthess-Lutz, Livio Baselgia, Kerstin Hansen, Raphael M Buzzi, Rok Humar, Elena Dürst, Florence Vallelian.
      Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in peri-necrotic hemorrhagic tumor regions. These cells resembled anti-inflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFNγ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance.
    Keywords:  Cancer; Inflammation; Innate immunity; Macrophages; Oncology
    DOI:  https://doi.org/10.1172/JCI174528
  4. J Trace Elem Med Biol. 2023 Dec 07. pii: S0946-672X(23)00232-8. [Epub ahead of print]82 127356
    Syringic acid alleviates cisplatin-induced ovarian injury through modulating endoplasmic reticulum stress, inflammation and Nrf2 pathway.
    Elif Ayazoglu Demir.
       BACKGROUND: Reproductive toxicity is one of the most important side effects of cisplatin (CIS) and leading to discontinuation of treatment. Syringic acid (SA) is a phenolic acid whose industrial use has increased in recent years due to its antioxidant properties. Recent reports highlight the importance of the supressed Nrf2 pathway in the molecular pathogenesis of CIS toxicity. Therefore, this study aimed to evaluate the therapeutic effect of SA on CIS-induced ovotoxicity through the Nrf2 pathway for the first time.
    MATERIAL AND METHODS: Thirty female rats were divided into 5 groups: control, CIS, CIS+SA (5 and 10 mg/kg) and only SA (per se, 10 mg/kg). CIS was administered intraperitoneally at a dose of 5 mg/kg on the 1st day, injections of SA followed by three consecutive days in the rats. Serum anti-mullerian hormone (AMH) levels and ovarian oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS), apoptosis and Nrf2 pathway markers were determined colorimetrically. Histopathological examinations of the ovaries with hematoxylin and eosin staining were also used to evaluate CIS-induced ovotoxicity.
    RESULTS: The CIS treatment depleted serum AMH levels, caused histopathological findings and increased OS, inflammation, ERS and apoptosis levels in ovarian tissue. However, treatments with SA significantly ameliorated CIS-induced biochemical and histopathological changes by activating Nrf2 pathway.
    CONCLUSION: The promising adjuvant potential of SA to alleviate CIS-related ovarian damage should be supported by more comprehensive studies.
    Keywords:  Cisplatin; Endoplasmic reticulum stress; Inflammation; Nrf2; Ovotoxicity; Oxidative stress; Syringic acid
    DOI:  https://doi.org/10.1016/j.jtemb.2023.127356
  5. Cell Death Discov. 2023 Dec 12. 9(1): 450
    Cepharanthine, a regulator of keap1-Nrf2, inhibits gastric cancer growth through oxidative stress and energy metabolism pathway.
    Yang-Yang Lu, Chun-Yang Zhu, Yi-Xin Ding, Bing Wang, Shu-Fen Zhao, Jing Lv, Shu-Ming Chen, Sha-Sha Wang, Yan Wang, Rui Wang, Wen-Sheng Qiu, Wei-Wei Qi.
      Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.
    DOI:  https://doi.org/10.1038/s41420-023-01752-z
  6. Free Radic Biol Med. 2023 Dec 11. pii: S0891-5849(23)01152-8. [Epub ahead of print]211 1-11
    Live-cell imaging Unveils stimulus-specific dynamics of Nrf2 activation in UV-exposed melanoma cells: Implications for antioxidant compound screening.
    Nilar Win Htut, Tasanee Onkoksoong, Malinee Saelim, Patipark Kueanjinda, Somponnat Sampattavanich, Uraiwan Panich.
      The transcription factor Nuclear factor e2-related factor 2 (Nrf2) is pivotal in orchestrating cellular antioxidant defense mechanisms, particularly in skin cells exposed to ultraviolet (UV) radiation and electrophilic phytochemicals. To comprehensively investigate Nrf2's role in maintaining cellular redox equilibrium following UV-induced stress, we engineered a novel Nrf2 fusion-based reporter system for real-time, live-cell quantification of Nrf2 activity in human melanoma cells. Utilizing live quantitative imaging, we dissected the kinetic profiles of Nrf2 activation in response to an array of stimuli, including UVA and UVB radiation, as well as a broad spectrum of phytochemicals including ferulic acid, gallic acid, hispidulin, p-coumaric acid, quercetin, resveratrol, tannic acid, and vanillic acid as well as well-known Nrf2 inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN). Intriguingly, we observed distinct dynamical patterns of Nrf2 activity contingent on the specific stimuli applied. Sustained activation of Nrf2 was empirically correlated with the increased antioxidant response element (ARE) activity. Our findings demonstrate the nuanced impact of different phenolic compounds on Nrf2 activity and the utility of our Nrf2-CTΔ16-YFP reporter in characterizing the dynamics of Nrf2 translocation in response to diverse stimuli. In summary, our innovative reporter system not only revealed compounds capable of modulating UVA-induced Nrf2 activity but also showcased its utility as a robust tool for future antioxidant compound screening efforts.
    Keywords:  Living cell-based biosensor; Nuclear factor erythroid 2-related factor 2 (Nrf2); Ultraviolet (UV) radiation; phytochemicals
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.007
  7. Environ Toxicol. 2023 Dec 08.
    Bardoxolone methyl attenuates doxorubicin-induced cardiotoxicity by inhibiting the TXNIP-NLRP3 pathway through Nrf2 activation.
    Wei Zhang, Chao Shi, Zhuoya Yao, Shaohuan Qian.
      Bardoxolone methyl, which triggers nuclear factor erythroid 2-related factor (Nrf2), has therapeutic effects against myocardial infarction, heart failure, and other diseases. Nrf2 can inhibit the activation of the thioredoxin-interacting protein (TXNIP)/NLR family pyrin domain-containing protein 3 (NLRP3) pathway. Doxorubicin is an anthracycline chemotherapeutic drug associated with cardiotoxicity, limiting its clinical use. In this study, we explored the specific mechanism of the Nrf2-TXNIP-NLRP3 pathway in doxorubicin-induced cardiotoxicity using bardoxolone methyl in animal and cell models. Using in vivo and in vitro experiments, we show that doxorubicin can induce oxidative stress and pyroptosis in the heart. Western blot and co-immunoprecipitation experimental results found that doxorubicin can reduce the interaction between TXNIP and TRX, increase the interaction between TXNIP and NLRP3, and activate the pyroptosis process. Bardoxolone methyl reduces the accumulation of reactive oxygen species in cardiomyocytes through the Nrf2 pathway, inhibits the interaction between TXNIP and NLRP3, and alleviates the progression of myocardial damage and cardiac fibrosis. Bardoxolone methyl lost its therapeutic effect when the expression of Nrf2 was decreased. Additionally, repressing the expression of TXNIP can inhibit the activation of NLRP3 and alleviate myocardial damage caused by doxorubicin. Collectively, our findings confirm that bardoxolone methyl alleviates doxorubicin-induced cardiotoxicity by activating Nrf2 and inhibiting the TXNIP-NLRP3 pathway.
    Keywords:  bardoxolone methyl; cardiotoxicity; doxorubicin; pyroptosis
    DOI:  https://doi.org/10.1002/tox.24075
  8. Int J Mol Sci. 2023 Dec 04. pii: 17111. [Epub ahead of print]24(23):
    Alpha-Lipoic Acid Reduces Cell Growth, Inhibits Autophagy, and Counteracts Prostate Cancer Cell Migration and Invasion: Evidence from In Vitro Studies.
    Sabrina Bossio, Anna Perri, Raffaella Gallo, Anna De Bartolo, Vittoria Rago, Daniele La Russa, Michele Di Dio, Sandro La Vignera, Aldo E Calogero, Giovanni Vitale, Antonio Aversa.
      Alpha-lipoic acid (ALA) is a natural antioxidant dithiol compound, exerting antiproliferative and antimetastatic effects in various cancer cell lines. In our study, we demonstrated that ALA reduces the cell growth of prostate cancer cells LNCaP and DU-145. Western blot results revealed that in both cancer cells, ALA, by upregulating pmTOR expression, reduced the protein content of two autophagy initiation markers, Beclin-1 and MAPLC3. Concomitantly, MTT assays showed that chloroquine (CQ) exposure, a well-known autophagy inhibitor, reduced cells' viability. This was more evident for treatment using the combination ALA + CQ, suggesting that ALA can reduce cells' viability by inhibiting autophagy. In addition, in DU-145 cells we observed that ALA affected the oxidative/redox balance system by deregulating the KEAP1/Nrf2/p62 signaling pathway. ALA decreased ROS production, SOD1 and GSTP1 protein expression, and significantly reduced the cytosolic and nuclear content of the transcription factor Nrf2, concomitantly downregulating p62, suggesting that ALA disrupted p62-Nrf2 feedback loop. Conversely, in LNCaP cells, ALA exposure upregulated both SOD1 and p62 protein expression, but did not affect the KEAP1/Nrf2/p62 signaling pathway. In addition, wound-healing, Western blot, and immunofluorescence assays evidenced that ALA significantly reduced the motility of LNCaP and DU-145 cells and downregulated the protein expression of TGFβ1 and vimentin and the deposition of fibronectin. Finally, a soft agar assay revealed that ALA decreased the colony formation of both the prostate cancer cells by affecting the anchorage independent growth. Collectively, our in vitro evidence demonstrated that in prostate cancer cells, ALA reduces cell growth and counteracts both migration and invasion. Further studies are needed in order to achieve a better understanding of the underlined molecular mechanisms.
    Keywords:  KEAP1; Nrf2; ROS; alpha-lipoic acid; autophagy; cell migration; p62; prostate cancer cells
    DOI:  https://doi.org/10.3390/ijms242317111
  9. J Enzyme Inhib Med Chem. 2024 Dec;39(1): 2290911
    Glutaminase inhibition as potential cancer therapeutics: current status and future applications.
    Rajath Cyriac, Kwangho Lee.
      Alterations in normal metabolic processes are defining features of cancer. Glutamine, an abundant amino acid in the human blood, plays a critical role in regulating several biosynthetic and bioenergetic pathways that support tumour growth. Glutaminolysis is a metabolic pathway that converts glutamine into various metabolites involved in the tricarboxylic acid (TCA) cycle and generates antioxidants that are vital for tumour cell survival. As glutaminase catalyses the initial step of this metabolic pathway, it is of great significance in cancer metabolism and tumour progression. Inhibition of glutaminase and targeting of glutaminolysis have emerged as promising strategies for cancer therapy. This review explores the role of glutaminases in cancer metabolism and discusses various glutaminase inhibitors developed as potential therapies for tumour regression.
    Keywords:  GLS; KEAP1 mutation; anticancer; cancer metabolism; glutaminase
    DOI:  https://doi.org/10.1080/14756366.2023.2290911
  10. Biomed Res Int. 2023 ;2023 9854915
    Retracted: A2/B1 Promotes NRF2 mRNA Stability and Inhibits Ferroptosis and Cell Proliferation in Breast Cancer Cells.
    BioMed Research International.
      [This retracts the article DOI: 10.1155/2023/2620738.].
    DOI:  https://doi.org/10.1155/2023/9854915
  11. Biomed Res Int. 2023 ;2023 9765743
    Retracted: Nestin Regulates Keap1-Nrf2-HO-1-Mediated Antioxidant Responses during Stress and Malignant Hematopoiesis.
    BioMed Research International.
      [This retracts the article DOI: 10.1155/2022/1706585.].
    DOI:  https://doi.org/10.1155/2023/9765743
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