bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023–07–09
seven papers selected by
Caner Geyik, Istinye University
  1. The promoting effect and mechanism of Nrf2 on cell metastasis in cervical cancer.
  2. Nuclear Factor Erythroid 2-Related Factor 2/Kelch-Like ECH-Associated Protein 1 as a Predictor of Prognosis and Radiotherapy Resistance in Patients With Locally Advanced Rectal Cancer: A Prospective Analysis.
  3. Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment.
  4. Sarmentosin Induces Autophagy-dependent Apoptosis via Activation of Nrf2 in Hepatocellular Carcinoma.
  5. The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2.
  6. Chemoprevention of lotus leaf ethanolic extract through epigenetic activation of the NRF2-mediated pathway in murine skin JB6 P+ cell neoplastic transformation.
  7. Retracted: mRNA-Modified FUS/NRF2 Signalling Inhibits Ferroptosis and Promotes Prostate Cancer Growth.
  1. J Transl Med. 2023 07 04. 21(1): 433
    The promoting effect and mechanism of Nrf2 on cell metastasis in cervical cancer.
    Mengwen Zhang, Xiaoling Hong, Ning Ma, Zhentong Wei, Xinxin Ci, Songling Zhang.
       BACKGROUND: Cervical cancer (CC) has poor prognosis and high mortality rate for its metastasis during the disease progression. Epithelial-mesenchymal transition (EMT) and anoikis are initial and pivotal steps during the metastatic process. Although higher levels of Nrf2 are associated with aggressive tumor behaviors in cervical cancer, the detailed mechanism of Nrf2 in cervical cancer metastasis, especially EMT and anoikis, remains unclear.
    METHODS: Immunohistochemistry (IHC) was used to examine Nrf2 expression in CC. Wound healing assay and transwell analysis were used to evaluate the migration ability of CC cells. Western blot, qTR-PCR and immunofluorescent staining were used to verify the expression level of Nrf2, the EMT associated markers and anoikis associated proteins. Flow cytometry assays and cell counting were used to detect the apoptosis of cervical cancer cells. The lung and lymph node metastatic mouse model were established for studies in vivo. The interaction between Nrf2 and Snail1 was confirmed by rescue-of-function assay.
    RESULTS: When compared with cervical cancer patients without lymph node metastasis, Nrf2 was highly expressed in patients with lymph node metastasis. And Nrf2 was proved to enhance the migration ability of HeLa and SiHa cells. In addition, Nrf2 was positively correlated with EMT processes and negatively associated with anoikis in cervical cancer. In vivo, a xenograft assay also showed that Nrf2 facilitated both pulmonary and lymphatic distant metastasis of cervical cancer. Rescue-of-function assay further revealed the mechanism that Nrf2 impacted the metastasis of CC through Snail1.
    CONCLUSION: Our fundings established Nrf2 plays a crucial role in the metastasis of cervical cancer by enhancing EMT and resistance to anoikis by promoting the expression of Snail1, with potential value as a therapeutic candidate.
    Keywords:  Anoikis; Cervical cancer (CC); Epithelial-mesenchymal transition (EMT); Neoplasm metastasis; Nuclear factor erythroid 2-related factor 2 (Nrf2, Nfe2l2)
    DOI:  https://doi.org/10.1186/s12967-023-04287-0
  2. J Korean Med Sci. 2023 Jul 03. 38(26): e200
    Nuclear Factor Erythroid 2-Related Factor 2/Kelch-Like ECH-Associated Protein 1 as a Predictor of Prognosis and Radiotherapy Resistance in Patients With Locally Advanced Rectal Cancer: A Prospective Analysis.
    Ji Min Park, Shin Kim, Sung Uk Bae, Sang Jun Byun, Incheol Seo, Hye Won Lee.
       BACKGROUND: The nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signaling pathway is involved in the regulation of cellular responses to oxidative stress. Nrf2 acts as a cell protector from inflammation, cellular damage, and tumorigenesis, whereas Keap1 is a negative regulator of Nrf2. Dysregulation of the Nrf2/Keap1 pathway results in tumorigenesis and the active metabolism of tumor cells, leading to high resistance to radiotherapy. This study aimed to evaluate the predictive role of Nrf2 and Keap1 in the radiosensitivity and prognosis of locally advanced rectal cancer (LARC).
    METHODS: In total, 90 patients with LARC underwent surgery after preoperative chemoradiotherapy (CRT). Endoscopic biopsies from the tumors were obtained before radiation, and the Nrf2 and Keap1 expressions were assessed by immunohistochemistry. The response to therapy was evaluated after surgery following CRT according to the pathologic tumor regression grade. The disease-free survival (DFS) and overall survival rates were also documented. The association between the Nrf2 and Keap1 immunoreactivity and the clinicopathological parameters was analyzed.
    RESULTS: The overexpression of the nuclear Nrf2 before CRT showed a significant correlation with better DFS. The cytoplasmic Nrf2 expression was associated with more residual tumors after radiotherapy and a more unfavorable DFS, indicating lower radiosensitivity.
    CONCLUSION: CRT is an important issue in LARC and is a major aspect of treatment. Thus, the Nrf2/Keap1 expression may be a potential predictor of preoperative therapeutic resistance. The Nrf2-Keap1 modulators that interact with each other may also be effectively applicable to CRT effect in LARC.
    Keywords:  Keap1; Nrf2; Radiation Therapy; Rectal Cancer; Tumor Regression
    DOI:  https://doi.org/10.3346/jkms.2023.38.e200
  3. Int J Biol Sci. 2023 ;19(10): 3029-3041
    Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment.
    Juan Zhang, Hong-Xi Xu, Jia-Qian Zhu, Yao-Xing Dou, Yan-Fang Xian, Zhi-Xiu Lin.
      Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates redox homeostasis, plays a pivotal role in several cellular processes such as cell proliferation and survival, and has been found to be aberrantly activated in many cancers. As one of the key oncogenes, Nrf2 represents an important therapeutic target for cancer treatment. Research has unraveled the main mechanisms underlying the Nrf2 pathway regulation and the role of Nrf2 in promoting tumorigenesis. Many efforts have been made to develop potent Nrf2 inhibitors, and several clinical trials are being conducted on some of these inhibitors. Natural products are well-recognized as a valuable source for development of novel therapeutics for cancer. So far, a number of natural compounds have been identified as Nrf2 inhibitors, such as apigenin, luteolin, and quassinoids compounds including brusatol and brucein D. These Nrf2 inhibitors have been found to mediate an oxidant response and display therapeutic effects in different types of human cancers. In this article, we reviewed the structure and function of the Nrf2/Keap1 system and the development of natural Nrf2 inhibitors with an emphasis on their biological function on cancer. The current status regarding the Nrf2 as a potential therapeutic target for cancer treatment was also summarized. It is hoped that this review will stimulate research on naturally occurring Nrf2 inhibitors as therapeutic candidates for cancer treatment.
    Keywords:  Brusatol; Cancer; Molecular target; Natural products; Nrf2 inhibitors
    DOI:  https://doi.org/10.7150/ijbs.82401
  4. J Clin Transl Hepatol. 2023 Aug 28. 11(4): 863-876
    Sarmentosin Induces Autophagy-dependent Apoptosis via Activation of Nrf2 in Hepatocellular Carcinoma.
    Zhitao Jiang, Liyuan Gao, Chundi Liu, Jianchun Wang, Yi Han, Jinhuo Pan.
       Background and Aims: Hepatocellular carcinoma (HCC) is a common and deadly cancer. Accumulating evidence supports modulation of autophagy as a novel approach for determining cancer cell fate. The aim of this study to evaluate the effectiveness of sarmentosin, a natural compound, on HCC in vitro and in vivo and elucidated the underlying mechanisms.
    Methods: Cell functions and signaling pathways were analyzed in HepG2 cells using western blotting, real-time PCR, siRNA, transmission electron microscopy and flow cytometry. BALB/c nude mice were injected with HepG2 cells to produce a xenograft tumour nude mouse model for in vivo assessments and their tumors, hearts, lungs and kidneys were isolated.
    Results: We found that autophagy was induced by sarmentosin in a concentration- and time-dependent manner in human HCC HepG2 cells by western blot assays and scanning electron microscopy. Sarmentosin-induced autophagy was abolished by the autophagy inhibitors 3-methyladenine, chloroquine, and bafilomycin A1. Sarmentosin activated Nrf2 in HepG2 cells, as shown by increased nuclear translocation and upregulated expression of Nrf2 target genes. Phosphorylation of mTOR was also inhibited by sarmentosin. Sarmentosin stimulated caspase-dependent apoptosis in HepG2 cells, which was impaired by silencing Nrf2 or chloroquine or knocking down ATG7. Finally, sarmentosin effectively repressed HCC growth in xenograft nude mice and activated autophagy and apoptosis in HCC tissues.
    Conclusions: This study showed sarmentosin stimulated autophagic and caspase-dependent apoptosis in HCC, which required activation of Nrf2 and inhibition of mTOR. Our research supports Nrf2 as a therapeutic target for HCC and sarmentosin as a promising candidate for HCC chemotherapy.
    Keywords:  Apoptosis; Autophagy; Hepatocellular carcinoma; Nrf2; Sarmentosin
    DOI:  https://doi.org/10.14218/JCTH.2022.00312
  5. Cell Rep. 2023 Jul 04. pii: S2211-1247(23)00735-0. [Epub ahead of print]42(7): 112724
    The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2.
    Julia Katharina Charlotte Kreß, Christina Jessen, Anita Hufnagel, Werner Schmitz, Thamara Nishida Xavier da Silva, Ancély Ferreira Dos Santos, Laura Mosteo, Colin R Goding, José Pedro Friedmann Angeli, Svenja Meierjohann.
      The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.
    Keywords:  ATF4; CHAC1; CP: Cell biology; GSH; NRF2; SLC7A11; integrated stress response; melanoma
    DOI:  https://doi.org/10.1016/j.celrep.2023.112724
  6. J Tradit Complement Med. 2023 Jul;13(4): 337-344
    Chemoprevention of lotus leaf ethanolic extract through epigenetic activation of the NRF2-mediated pathway in murine skin JB6 P+ cell neoplastic transformation.
    Yen-Chen Tung, Ping-Hua Sung, Pei-Chun Chen, Hsiao Chi Wang, Jong Hun Lee, Zheng-Yuan Su.
       Background and aim: Skin is one barrier protecting from environmental risk factors that can make skin cells cancerous through DNA damage and oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is an anti-stress defense system that can be regulated by DNA methylation and histone modification. Dietary phytochemicals have chemopreventive properties that can inhibit or delay carcinogenesis. The lotus leaf is a traditional medicinal plant containing many polyphenols whose extracts show many biological activities, including antioxidant, anti-obesity, and anti-cancer. This study aim to investigate the effect of lotus leaves on neoplastic transformation in murine skin JB6 P+ cells.
    Experimental procedure: Lotus leaves were extracted with water (LL-WE) and ethanol (LL-EE), and the LL-WE residues were further extracted with ethanol (LL-WREE). JB6 P+ cells were treated with different extracts. The chemoprotective effect would be evaluated by heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase (NQO1), and UDP glucuronosyltransferase family 1 member A1 (UGT1A1) expression.
    Results and conclusion: LL-EE contained higher total phenolics and quercetin among extracts. In mouse skin JB6 P+ cells with 12-O-tetradecanoylphorbol-13-acetate treatment, LL-EE showed the greatest potential to suppress skin carcinogenesis. LL-EE activated the NRF2 pathway by upregulating antioxidant and detoxification enzymes upregulates antioxidant and detoxification enzymes, including HO-1, NQO1, and UGT1A1, and downregulates DNA methylation, which might be caused by lower DNA methyltransferase and histone deacetylase levels. Therefore, our results show that LL-EE reduces the neoplastic transformation of skin JB6 P+ cells, potentially by activating the NRF2 pathway and regulating epigenetic DNA methylation and histone acetylation.
    Keywords:  Antioxidant; Cancer transformation; DNA methylation; Herbal medicine; Skin cell
    DOI:  https://doi.org/10.1016/j.jtcme.2023.02.002
  7. Comput Math Methods Med. 2023 ;2023 9804615
    Retracted: mRNA-Modified FUS/NRF2 Signalling Inhibits Ferroptosis and Promotes Prostate Cancer Growth.
    Computational And Mathematical Methods In Medicine.
      [This retracts the article DOI: 10.1155/2022/8509626.].
    DOI:  https://doi.org/10.1155/2023/9804615
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