bims-nurfca 2024-08-04 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024‒08‒04
nine papers selected by
Caner Geyik, Istinye University

Pharmacologic inhibition of eIF4A blocks NRF2 synthesis to prevent osteosarcoma metastasis.
Overexpression of Nrf2 in bone marrow mesenchymal stem cells promotes B-cell acute lymphoblastic leukemia cells invasion and extramedullary organ infiltration through stimulation of the SDF-1/CXCR4 axis.
DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells.
Enhancement of chemoresistance by claudin-1-mediated formation of amino acid barriers in human lung adenocarcinoma A549 cells.
Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis.
Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors.
Transcriptomics pave the way into mechanisms of cobalt and nickel toxicity: Nrf2-mediated cellular responses in liver carcinoma cells.
[Retracted] Allicin suppresses the migration and invasion in cervical cancer cells mainly by inhibiting NRF2.
State-of-the-art Nrf2 Inhibitors: Therapeutic Opportunities in Non-cancer Diseases.

Clin Cancer Res. 2024 Jul 30.

Pharmacologic inhibition of eIF4A blocks NRF2 synthesis to prevent osteosarcoma metastasis.

Michael M Lizardo, Christopher Hughes, Yue Z Huang, Taras Shyp, Alberto Delaidelli, Hai-Feng Zhang, Sol Snir Shaool, Annalena F Renner, Fares Burwag, Leanne C Sayles, Alex G Lee, E Alejandro Sweet-Cordero, Poul H Sorensen.

PURPOSE: Effective therapies for metastatic osteosarcoma (OS) remain a critical unmet need. Targeting mRNA translation in metastatic OS offers a promising option, as selective translation drives synthesis of cytoprotective proteins under harsh microenvironmental conditions to facilitate metastatic competence.EXPERIMENTAL DESIGN: We assessed expression levels of eukaryotic translation factors in OS, revealing high expression of the eIF4A1 initiation factor. Using a panel of metastatic OS cell lines and PDX models, eIF4A1 inhibitors were evaluated for their ability to block proliferation and reduce survival under oxidative stress, mimicking harsh conditions of the lung microenvironment. Inhibitors were also evaluated for their anti-metastatic activity using the ex vivo pulmonary metastasis assay (PuMA) and in vivo metastasis models. Proteomics were performed to catalog which cytoprotective proteins or pathways were affected by eIF4A1 inhibition.
RESULTS: CR-1-31B, a rocaglate-based eIF4A1 inhibitor, exhibited nanomolar cytotoxicity against all metastatic OS models tested. CR-1-31B exacerbated oxidative stress and apoptosis when OS cells were co-treated with a tert-butylhydroquinone (tBHQ), a chemical oxidative stress inducer. CR-1-31B potently inhibited OS growth in the PuMA model and in experimental and spontaneous models of OS lung metastasis. Proteomic analysis revealed that tBHQ-mediated upregulation of the NRF2 antioxidant factor was blocked by co-treatment with CR-1-31B. Genetic inactivation of NRF2 phenocopied the anti-metastatic activity of CR-1-31B. Finally, the clinical grade eIF4A1 phase 1-2 inhibitor, Zotatifin, similarly blocked NRF2 synthesis and the OS metastatic phenotype.
CONCLUSIONS: Collectively, our data reveal that pharmacologic targeting of eIF4A1 is highly effective in blocking OS metastasis by blunting the NRF2 antioxidant response.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1317
Front Pharmacol. 2024 ;15 1393482

Overexpression of Nrf2 in bone marrow mesenchymal stem cells promotes B-cell acute lymphoblastic leukemia cells invasion and extramedullary organ infiltration through stimulation of the SDF-1/CXCR4 axis.

Lin Zheng, Chengyun Pan, Dan Ma, Qin Shang, Tianzhen Hu, Tianzhuo Zhang, Qian Kang, Xiuying Hu, Shuyun Cao, Li Wang, Hong Luo, Jishi Wang.

  Background: Tumor microenvironment (TME) represents the key factor inducing leukemia development. As stromal cells within the leukemia microenvironment, Bone Marrow Mesenchymal Stem Cells (BM-MSCs) can trigger leukemia progression under certain conditions. As a critical transcription factor, nuclear factor erythroid related factor 2 (Nrf2) can modulate antioxidant response and antioxidant enzyme gene expression, and prevent various oxidative changes. We previously identified a novel mechanism by which Nrf2 promotes leukemia resistance, providing a potential therapeutic target for the treatment of drug-resistant/refractory leukemias. However, the role of Nrf2 in BM-MSCs from B-cell acute lymphoblastic leukemia (B-ALL) patients has not been clearly reported. The present work focused on investigating the effect of Nrf2 overexpression within MSCs on leukemia cell invasion, extramedullary infiltration and proliferation as well as its downstream pathway.Methods: Through clinical sample detection, in vitro cell experiments and in vivo animal experiments, the role of Nrf2 within MSCs within adult B-ALL cell migration and invasion and its potential molecular mechanism was explored through transcriptome sequencing analysis, RT-PCR, Western blot, cell migration, cell invasion, lentivirus transfection and other experiments.
Results: Nrf2 was highly expressed in BM-MSCs from patients with B-ALL as well as in BM-MSCs co-cultured with leukemia cells. Overexpression of Nrf2 within MSCs significantly promoted leukemia cell migration, invasion and proliferation. The extramedullary organ infiltration rate in B-ALL model mice receiving the combined infusion of both cell types dramatically increased relative to that of leukemia cells alone, accompanied by the significantly shortened survival time. Mechanism study found that Nrf2 overexpression within MSCs promoted PI3K-AKT/ERK1/2 phosphorylation in the downstream pathway by activating SDF-1/CXCR4 axis, ultimately leading to extramedullary infiltration of leukemia cells.
Conclusion: High Nrf2 expression with in MSCs enhances leukemia cell invasion and migration, which then accelerates infiltration in leukemic extramedullary organs. Targeting Nrf2 or inhibiting its downstream signal molecules may be the effective interventions for B-ALL patients treatment.

Keywords:  B-acute lymphocytic leukemia; MSCs; Nrf2; SDF-1/CXCR4; extramedullary infiltration

DOI:  https://doi.org/10.3389/fphar.2024.1393482
Redox Biol. 2024 Jul 29. pii: S2213-2317(24)00270-2. [Epub ahead of print]75 103292

DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells.

Yunjiang Zhou, Yaxin Chen, Chenyuan Xuan, Xingyan Li, Yingying Tan, Mengdi Yang, Mengran Cao, Chi Chen, Xing Huang, Rong Hu.

  Chemotherapy has been the standard treatment for liver cancer. However, intrinsic or acquired drug resistance remains a major barrier to successful treatment. At present, the underlying molecular mechanisms of chemoresistance in liver cancer have not been elucidated. Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family that has been found to be highly expressed in a variety of tumors, including liver cancer. It is unclear whether DPP9 affects chemoresistance in liver cancer. In this study, we find that DPP9 weakens the responses of liver cancer cells to chemotherapy drugs by up-regulating NQO1 and inhibiting intracellular ROS levels. In terms of mechanism, DPP9 inhibits ubiquitin-mediated degradation of NRF2 protein by binding to KEAP1, up-regulates NRF2 protein levels, promotes mRNA transcription of NQO1, and inhibits intracellular ROS levels. In addition, the NQO1 inhibitor dicoumarol can enhance the efficacy of chemotherapy drugs in liver cancer cells. Collectively, our findings suggest that inhibiting DPP9/NQO1 signaling can serve as a potential therapeutic strategy for liver cancer.

Keywords:  DPP9; Drug resistance; Liver cancer; NQO1; ROS

DOI:  https://doi.org/10.1016/j.redox.2024.103292
Arch Biochem Biophys. 2024 Jul 25. pii: S0003-9861(24)00228-5. [Epub ahead of print] 110106

Enhancement of chemoresistance by claudin-1-mediated formation of amino acid barriers in human lung adenocarcinoma A549 cells.

Riho Kimura, Shotaro Hashimoto, Hiroaki Eguchi, Yoshifumi Morikawa, Koichi Suenami, Yuta Yoshino, Toshiyuki Matsunaga, Satoshi Endo, Akira Ikari.

  Claudin-1 (CLDN1) is highly expressed in human lung adenocarcinoma-derived A549 cells and is involved in the augmentation of chemoresistance. However, the mechanism of chemoresistance is not fully understood. In the tumor microenvironment, cancer cells are exposed to stress conditions such as hypoxia and malnutrition. Here, we investigated the effect of CLDN1 expression on amino acid (AA) flux and chemoresistance using A549 cells. The expression of L-type AA transporters, LAT1 and LAT3, was decreased by CLDN1 silencing in A549 spheroids. A reduction in extracellular AA concentration increased the expression of these AA transporters in two-dimensional (2D) cultured cells. The paracellular AA flux except for Ser, Thr, Tyr, Ala, and Gly was enhanced by CLDN1 silencing. These results suggest that CLDN1 forms a paracellular barrier to some AAs, leading to the elevation of LAT1/3 expression in spheroids. The production of reactive oxygen species in the mitochondria and cytosol was decreased by CLDN1 silencing in spheroids, resulting in downregulation of the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target antioxidant genes. CLDN1 silencing enhanced the cytotoxicity of anticancer drugs including doxorubicin and cisplatin, which was blocked by sulforaphane, an inducer of Nrf2 signaling. Similarly, the anticancer-induced toxicity was enhanced by Nrf2 silencing. In 2D cultured cells, the anticancer-induced toxicity was attenuated by AA deficiency and sulforaphane. We suggest that CLDN1 forms an AA barrier in spheroids, leading to the augmentation of Nrf2-dependent chemoresistance in A549 cells.

Keywords:  amino acid transport; chemoresistance; claudin-1

DOI:  https://doi.org/10.1016/j.abb.2024.110106
Acta Pharmacol Sin. 2024 Aug 01.

Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis.

Chun-Yu Hou, Yu-Hong Suo, Pan Lv, Hong-Feng Yuan, Li-Na Zhao, Yu-Fei Wang, Hui-Hui Zhang, Jiao Sun, Lin-Lin Sun, Wei Lu, Ning-Ning Zhang, Guang Yang, Xiao-Dong Zhang.

  Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.

Keywords:  GADD45A; NRF2; aristolochic acids; ferroptosis; hepatocellular carcinoma; p53

DOI:  https://doi.org/10.1038/s41401-024-01354-0
Immunity. 2024 Jul 25. pii: S1074-7613(24)00353-4. [Epub ahead of print]

Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors.

Hannah L Erickson, Sachiko Taniguchi, Anish Raman, Justin J Leitenberger, Sanjay V Malhotra, Naoki Oshimori.

  In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an "eat me" signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B's scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.

Keywords:  ATG9b; FPR2; IL-33; annexin A1; cancer stem cell niche; cancer stem cells; large oncosomes; macrophages; squamous cell carcinoma; tumor microenvironment

DOI:  https://doi.org/10.1016/j.immuni.2024.07.004
Redox Biol. 2024 Jul 27. pii: S2213-2317(24)00268-4. [Epub ahead of print]75 103290

Transcriptomics pave the way into mechanisms of cobalt and nickel toxicity: Nrf2-mediated cellular responses in liver carcinoma cells.

Alicia Thiel, Franziska Drews, Marcello Pirritano, Fabian Schumacher, Vivien Michaelis, Maria Schwarz, Sören Franzenburg, Tanja Schwerdtle, Bernhard Michalke, Anna P Kipp, Burkhard Kleuser, Martin Simon, Julia Bornhorst.

  Cobalt (Co) and Nickel (Ni) are used nowadays in various industrial applications like lithium-ion batteries, raising concerns about their environmental release and public health threats. Both metals are potentially carcinogenic and may cause neurological and cardiovascular dysfunctions, though underlying toxicity mechanisms have to be further elucidated. This study employs untargeted transcriptomics to analyze downstream cellular effects of individual and combined Co and Ni toxicity in human liver carcinoma cells (HepG2). The results reveal a synergistic effect of Co and Ni, leading to significantly higher number of differentially expressed genes (DEGs) compared to individual exposure. There was a clear enrichment of Nrf2 regulated genes linked to pathways such as glycolysis, iron and glutathione metabolism, and sphingolipid metabolism, confirmed by targeted analysis. Co and Ni exposure alone and combined caused nuclear Nrf2 translocation, while only combined exposure significantly affects iron and glutathione metabolism, evidenced by upregulation of HMOX-1 and iron storage protein FTL. Both metals impact sphingolipid metabolism, increasing dihydroceramide levels and decreasing ceramides, sphingosine and lactosylceramides, along with diacylglycerol accumulation. By combining transcriptomics and analytical methods, this study provides valuable insights into molecular mechanisms of Co and Ni toxicity, paving the way for further understanding of metal stress.

Keywords:  Cobalt; Metal interactions; Nickel; Nrf2 signaling; Sphingolipid metabolism; Transcriptomic analysis

DOI:  https://doi.org/10.1016/j.redox.2024.103290
Exp Ther Med. 2024 Oct;28(4): 370

[Retracted] Allicin suppresses the migration and invasion in cervical cancer cells mainly by inhibiting NRF2.

Qiumei Zhang, Dongmei Yang.

[This retracts the article DOI: 10.3892/etm.2018.7104.].

DOI: https://doi.org/10.3892/etm.2024.12659
ChemMedChem. 2024 Jul 31. e202400377

State-of-the-art Nrf2 Inhibitors: Therapeutic Opportunities in Non-cancer Diseases.

Matteo Borgini, Emil G Ayala-Cosme, Deborah Yang, Kyara Vences, Lindsey O Davis.

  Nrf2 is a cytoprotective transcription factor that induces the transcription of genes responsible for the cell's response to oxidative stress. While Nrf2 activation has led to the development of clinically relevant therapeutics, the oncogenic role of Nrf2 in the proliferation of cancer cells has underscored the complex nature of Nrf2 and the necessity for the development of Nrf2 inhibitors. Although the application of Nrf2 inhibitors appears limited as anticancer agents, recent studies have begun to pinpoint the impairment of autophagy in diseases as a cellular marker that shifts Nrf2 from a protective to a deleterious state. Therefore, the cytoplasmic accumulation of Nrf2 can lead to the accumulation of lipid hydroperoxides and, ultimately, to ferroptosis. However, some studies aimed at elucidating the role of Nrf2 in non-cancer diseases have yielded conflicting results, attributed to differences in approaches used to inhibit or activate Nrf2, as well as variations in disease models. Overall, these results highlight the necessity for a deeper evaluation of Nrf2's role in diseases, especially chronic diseases. In this review, we discuss diseases where Nrf2 inhibition holds potential for beneficial therapeutic effects and summarize recently reported Nrf2 inhibitors exploiting medicinal chemistry approaches suitable for targeting transcription factors like Nrf2.

Keywords:  Nrf2 inhibitors * Nuclear factor erythroid 2-related factor * Autophagy * Ferroptosis * Transcription factor

DOI:  https://doi.org/10.1002/cmdc.202400377