bims-nurfca 2024-06-30 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024‒06‒30
ten papers selected by
Caner Geyik, Istinye University

The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer.
Fucoxanthin Induces Ferroptosis in Cancer Cells via Downregulation of the Nrf2/HO-1/GPX4 Pathway.
Downregulation of chemoresistance by claudin-14 silencing in human colorectal cancer cells.
The Triterpenoid CDDO-Methyl Ester Reduces Tumor Burden, Reprograms the Immune Microenvironment, and Protects from Chemotherapy-Induced Toxicity in a Preclinical Mouse Model of Established Lung Cancer.
MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2.
Early onset colorectal cancer: Cancer promotion in young tissue.
Role of the Nrf2/ARE Pathway in the mtDNA Reparation.
Dual Effect by Chemical Electron Transfer Enhanced siRNA Lipid Nanoparticles: Reactive Oxygen Species-Triggered Tumor Cell Killing Aggravated by Nrf2 Gene Silencing.
Dietary isothiocyanates and anticancer agents: exploring synergism for improved cancer management.
DDIT3 is associated with breast cancer prognosis and immune microenvironment: an integrative bioinformatic and immunohistochemical analysis.

Antioxidants (Basel). 2024 Jun 06. pii: 696. [Epub ahead of print]13(6):

The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer.

Dinara Baiskhanova, Heiner Schäfer.

  The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) represents the master regulator of the cellular antioxidant response and plays a critical role in tumorigenesis. This includes a preventive effect of Nrf2 on cell death through ferroptosis, which represents an essential mechanism of therapy resistance in malignant tumors, such as pancreatic ductal adenocarcinoma (PDAC) as one of the most aggressive and still incurable tumors. Addressing this issue, we provide an overview on Nrf2 mediated antioxidant response with particular emphasis on its effect on mitochondria as the organelle responsible for the execution of ferroptosis. We further outline how deregulated Nrf2 adds to the progression and therapy resistance of PDAC, especially with respect to the role of ferroptosis in anti-cancer drug mediated cell killing and how this is impaired by Nrf2 as an essential mechanism of drug resistance. Our review further discusses recent approaches for Nrf2 inhibition by natural and synthetic compounds to overcome drug resistance based on enhanced ferroptosis. Finally, we provide an outlook on therapeutic strategies based on Nrf2 inhibition combined with ferroptosis inducing drugs.

Keywords:  Nrf2; antioxidant genes; ferroptosis; mitochondria; oxidative stress; pancreatic cancer

DOI:  https://doi.org/10.3390/antiox13060696
Molecules. 2024 Jun 14. pii: 2832. [Epub ahead of print]29(12):

Fucoxanthin Induces Ferroptosis in Cancer Cells via Downregulation of the Nrf2/HO-1/GPX4 Pathway.

Hao-Fei Du, Jia-Wei Wu, Yu-Shan Zhu, Zheng-Hao Hua, Si-Zhou Jin, Jin-Chao Ji, Cai-Sheng Wang, Guo-Ying Qian, Xu-Dong Jin, Hao-Miao Ding.

  This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory effects of fucoxanthin on SCC-25 human tongue squamous carcinoma cells. The levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and total iron were measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to assess glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (Nrf2), Keap1, solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein 1 (TFR1), p53, and heme oxygenase 1 (HO-1) expression. Molecular docking was performed to validate interactions. Compared with the control group, the activity of fucoxanthin-treated SCC-25 cells significantly decreased in a dose- and time-dependent manner. The levels of MMP, GSH, and SOD significantly decreased in fucoxanthin-treated SCC-25 cells; the levels of ROS, MDA, and total iron significantly increased. mRNA and protein expression levels of Keap1, GPX4, Nrf2, and HO-1 in fucoxanthin-treated cells were significantly decreased, whereas levels of TFR1 and p53 were significantly increased, in a concentration-dependent manner. Molecular docking analysis revealed that binding free energies of fucoxanthin with p53, SLC7A11, GPX4, Nrf2, Keap1, HO-1, and TFR1 were below -5 kcal/mol, primarily based on active site hydrogen bonding. Our findings suggest that fucoxanthin can induce ferroptosis in SCC-25 cells, highlighting its potential as a treatment for tongue cancer.

Keywords:  Nrf2/HO−1/GPX4 pathway; anti−cancer; ferroptosis; fucoxanthin

DOI:  https://doi.org/10.3390/molecules29122832
Arch Biochem Biophys. 2024 Jun 26. pii: S0003-9861(24)00196-6. [Epub ahead of print] 110075

Downregulation of chemoresistance by claudin-14 silencing in human colorectal cancer cells.

Yuko Mizukami, Ayaka Ito, Shotaro Hashimoto, Tomoka Ando, Yoshinobu Ishikawa, Hiroaki Eguchi, Yuta Yoshino, Toshiyuki Matsunaga, Akira Ikari.

  An exceptional expression of claudins (CLDNs), tight junction (TJ) proteins, is observed in various solid cancer tissues. However, the pathophysiological roles of CLDNs have not been clarified in detail. CLDN14 is highly expressed in human colorectal cancer (CRC) tissues and cultured cancer epithelial cells. We found CLDN14 silencing decreased cell viability without affecting spheroid size in the three-dimensional (3D) spheroid model of DLD-1 cells derived from human CRC. Mitochondria activity and oxidative stress level were reduced by CLDN14 silencing. Furthermore, CLDN14 silencing decreased the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target antioxidative genes. CLDN14 was colocalized with ZO-1, a scaffolding protein in the TJ. CLDN14 silencing induced the disruption of TJ barrier such as the reduction of transepithelial electrical resistance and elevation of fluxes of small molecules including glucose in two-dimensional (2D) cultured model,. The depletion of glucose induced the elevation of ROS generation, mitochondria activity, and Nrf2 expression. These results suggest that CLDN14 increases Nrf2 expression in spheroids mediated via the formation of paracellular barrier to glucose. The cytotoxicities of doxorubicin, an anthracycline anticancer drug, and oxaliplatin, a platinum-based agent, were augmented by an Nrf2 activator in 2D cultured cells. The anticancer drug-induced toxicity was enhanced by CLDN14 silencing in 3D spheroids. We suggest that CLDN14 may potentiate chemoresistance mediated by the suppression of paracellular glucose permeability and activation of the Nrf2 signaling pathway in CRC cells.

Keywords:  chemoresistance; claudin-14; colorectal cancer

DOI:  https://doi.org/10.1016/j.abb.2024.110075
Antioxidants (Basel). 2024 May 21. pii: 621. [Epub ahead of print]13(6):

The Triterpenoid CDDO-Methyl Ester Reduces Tumor Burden, Reprograms the Immune Microenvironment, and Protects from Chemotherapy-Induced Toxicity in a Preclinical Mouse Model of Established Lung Cancer.

Jessica A Moerland, Karen T Liby.

  NRF2 activation protects epithelial cells from malignancy, but cancer cells can upregulate the pathway to promote survival. NRF2 activators including CDDO-Methyl ester (CDDO-Me) inhibit cancer in preclinical models, suggesting NRF2 activation in other cell types may promote anti-tumor activity. However, the immunomodulatory effects of NRF2 activation remain poorly understood in the context of cancer. To test CDDO-Me in a murine model of established lung cancer, tumor-bearing wildtype (WT) and Nrf2 knockout (KO) mice were treated with 50-100 mg CDDO-Me/kg diet, alone or combined with carboplatin/paclitaxel (C/P) for 8-12 weeks. CDDO-Me decreased tumor burden in an Nrf2-dependent manner. The combination of CDDO-Me plus C/P was significantly (p < 0.05) more effective than either drug alone, reducing tumor burden by 84% in WT mice. CDDO-Me reduced the histopathological grade of WT tumors, with a significantly (p < 0.05) higher proportion of low-grade tumors and a lower proportion of high-grade tumors. These changes were augmented by combination with C/P. CDDO-Me also protected WT mice from C/P-induced toxicity and improved macrophage and T cell phenotypes in WT mice, reducing the expression of CD206 and PD-L1 on macrophages, decreasing immunosuppressive FoxP3+ CD4+ T cells, and increasing activation of CD8+ T cells in a Nrf2-dependent manner.

Keywords:  CDDO-Methyl ester; carboplatin; chemotherapy; immunomodulation; lung cancer; paclitaxel; triterpenoid; tumor microenvironment

DOI:  https://doi.org/10.3390/antiox13060621
Cell Prolif. 2024 Jun 26. e13700

MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2.

Xiao Han, Yupeng Zhang, Yin Li, Zhoujun Lin, Zhenkun Fu, Changjun Wang, Shengjie Zhang, Di Shao, Chenggang Li.

Tamoxifen resistance is a common and difficult problem in the clinical treatment of breast cancer (BC). As a novel antitumor agent, Micheliolide (MCL) has shown a better therapeutic effect on tumours; however, little is known about MCL and its role in BC therapy. With tamoxifen stimulation, drug-resistant BC cells MCF7TAMR and T47DTAMR obtained a high oxidative status and Amidohydrolase 1 (ASAH1) was abnormally activated. The inhibition of ASAH1 rescued the sensitivity of resistant cells to tamoxifen. We found that MCL inhibited the expression of ASAH1 and cell proliferation, especially in MCF7TAMR and T47DTAMR cells. The high oxidative stress status of resistant cells stimulated the expression of ASAH1 by positively regulating AKT, which was restrained by MCL. MCL activated NRF2 by directly binding to KEAP1 and promoting the antioxidant level of tamoxifen-resistant (TAMR) cells. In addition, ACT001, the prodrug of MCL, significantly inhibited the tumour growth of TAMR cells in preclinical xenograft tumour models. In conclusion, ASAH1 mediates tamoxifen resistance in ER-positive BC cells. MCL could activate the cellular antioxidant system via NRF2/KEAP1 and inhibit ASAH1 expression through the ROS/AKT signalling pathway, thus suppressing cell proliferation. MCL could be used as a potential treatment for TAMR-BC.

DOI: https://doi.org/10.1111/cpr.13700
Biochem Pharmacol. 2024 Jun 26. pii: S0006-2952(24)00376-9. [Epub ahead of print] 116393

Early onset colorectal cancer: Cancer promotion in young tissue.

Charles Giardina, Alan Kuo, Klea Nito, Shan Kurkcu.

  The incidence of colorectal cancer (CRC) in patients under 50 has been increasing over the past several decades. The factors underlying the increase in early onset colorectal cancer (EOCRC) are not entirely clear, although several genetic and clinical differences with late onset colorectal cancer (LOCRC) have been noted. EOCRC cases are often diagnosed at a more advanced stage, raising the possibility that these cancers progress more rapidly than LOCRC cases. The impact of age on cancer progression is an intriguing topic and numerous lines of research have found that a young tissue environment is often more promotional. In fact, a less hospitable promotional tissue environment in older individuals may offset the increased cancer risk associated with the increased mutational load associated with age. Here we address how youthful aspects of angiogenesis, the tumor immune response, and the oxidative stress response may contribute to the rapid progression of EOCRC. Understanding the factors promoting EOCRC may provide insight into why EOCRC cases are increasing.

Keywords:  Angiogenesis; Antioxidant response; Cancer promotion; Early onset colorectal cancer; Glutathione; Nrf2; Tumor immune response

DOI:  https://doi.org/10.1016/j.bcp.2024.116393
Front Biosci (Landmark Ed). 2024 Jun 18. 29(6): 218

Role of the Nrf2/ARE Pathway in the mtDNA Reparation.

Artem P Gureev, Ekaterina V Chernyshova, Ekaterina P Krutskikh, Irina S Sadovnikova, Elena E Tekutskaya, Anna A Dorohova.

  Mitochondrial DNA (mtDNA) is located in the mitochondrial matrix, in close proximity to major sources of reactive oxygen species (ROS) in the cell. This makes mtDNA one of the most susceptible components to damage in the cell. The nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is an important cytoprotective mechanism. It is well-studied and described that Nrf2 can regulate the expression of mitochondrial-targeted antioxidant systems in the cell, indirectly protecting mtDNA from damage. However, the Nrf2/ARE pathway can also directly impact on the mtDNA repair processes. In this review, we summarize the existing data on the impact of Nrf2 on mtDNA repair, primarily base excision repair (BER), as it is considered the main repair pathway for the mitochondrial genome. We explore the crosstalk between Nrf2/ARE, BRCA1, and p53 signaling pathways in their involvement in maintaining mtDNA integrity. The role of other repair mechanisms in correcting mismatched bases and double-strand breaks is discussed. Additionally, the review addresses the role of Nrf2 in the repair of noncanonical bases, which contribute to an increased number of mutations in mtDNA and can contaminate the nucleotide pool.

Keywords:  BRCA1; Nrf2/ARE pathway; base excision repair; mtDNA; p53

DOI:  https://doi.org/10.31083/j.fbl2906218
Pharmaceutics. 2024 Jun 07. pii: 779. [Epub ahead of print]16(6):

Dual Effect by Chemical Electron Transfer Enhanced siRNA Lipid Nanoparticles: Reactive Oxygen Species-Triggered Tumor Cell Killing Aggravated by Nrf2 Gene Silencing.

Fengrong Zhang, Tobias Burghardt, Miriam Höhn, Ernst Wagner.

  Insufficient endosomal escape presents a major hurdle for successful nucleic acid therapy. Here, for the first time, a chemical electron transfer (CET) system was integrated into small interfering RNA (siRNA) lipid nanoparticles (LNPs). The CET acceptor can be chemically excited using the generated energy between the donor and hydrogen peroxide, which triggers the generation of reactive oxygen species (ROS), promoting endosomal lipid membrane destabilization. Tetra-oleoyl tri-lysino succinoyl tetraethylene pentamine was included as an ionizable lipopeptide with a U-shaped topology for effective siRNA encapsulation and pH-induced endosomal escape. LNPs loaded with siRNA and CET components demonstrated a more efficient endosomal escape, as evidenced by a galectin-8-mRuby reporter; ROS significantly augmented galectin-8 recruitment by at least threefold compared with the control groups, with a p value of 0.03. Moreover, CET-enhanced LNPs achieved a 24% improvement in apoptosis level by knocking down the tumor-protective gene nuclear factor erythroid 2-related factor 2, boosting the CET-mediated ROS cell killing.

Keywords:  chemical electron transfer; endosomal escape; lipid nanoparticles; reactive oxygen species; small interfering RNA

DOI:  https://doi.org/10.3390/pharmaceutics16060779
Front Nutr. 2024 ;11 1386083

Dietary isothiocyanates and anticancer agents: exploring synergism for improved cancer management.

Qi Wang, Dan Li, Lihua Liu, Yujuan Shan, Yongping Bao.

  Human studies have shown the anticancer effects of dietary isothiocyanates (ITCs), but there are some inconsistencies, and more evidence supports that such anticancer effect is from higher doses of ITCs. The inconsistencies found in epidemiological studies may be due to many factors, including the biphasic dose-response (so called hormetic effect) of ITCs, which was found to be more profound under hypoxia conditions. In this comprehensive review, we aim to shed light on the intriguing synergistic interactions between dietary ITCs, focusing on sulforaphane (SFN) and various anticancer drugs. Our exploration is motivated by the potential of these combinations to enhance cancer management strategies. While the anticancer properties of ITCs have been recognized, our review delves deeper into understanding the mechanisms and emphasizing the significance of the hormetic effect of ITCs, characterized by lower doses stimulating both normal cells and cancer cells, whereas higher doses are toxic to cancer cells and inhibit their growth. We have examined a spectrum of studies unraveling the multifaceted interaction and combinational effects of ITCs with anticancer agents. Our analysis reveals the potential of these synergies to augment therapeutic efficacy, mitigate chemoresistance, and minimize toxic effects, thereby opening avenues for therapeutic innovation. The review will provide insights into the underlying mechanisms of action, for example, by spotlighting the pivotal role of Nrf2 and antioxidant enzymes in prevention. Finally, we glimpse ongoing research endeavors and contemplate future directions in this dynamic field. We believe that our work contributes valuable perspectives on nutrition and cancer and holds promise for developing novel and optimized therapeutic strategies.

Keywords:  anticancer drugs; cancer management; chemoprevention; isothiocyanates; sulforaphane; synergistic interactions

DOI:  https://doi.org/10.3389/fnut.2024.1386083
J Cancer. 2024 ;15(12): 3873-3889

DDIT3 is associated with breast cancer prognosis and immune microenvironment: an integrative bioinformatic and immunohistochemical analysis.

Xin Yu, Wenge Li, Shengrong Sun, Juanjuan Li.

  DNA damage-inducible transcript 3 (DDIT3) is a transcription factor central to apoptosis, differentiation, and stress response. DDIT3 has been extensively studied in cancer biology. However, its precise implications in breast cancer progression and its interaction with the immune microenvironment are unclear. In this study, we utilized a novel multi-omics integration strategy, combining bulk RNA sequencing, single-cell sequencing, spatial transcriptomics and immunohistochemistry, to explore the role of DDIT3 in breast cancer and establish the correlation between DDIT3 and poor prognosis in breast cancer patients. We identified a robust prognostic signature, including six genes (unc-93 homolog B1, TLR signaling regulator, anti-Mullerian hormone, DCTP pyrophosphatase 1, mitochondrial ribosomal protein L36, nuclear factor erythroid 2, and Rho GTPase activating protein 39), associated with DDIT3. This signature stratified the high-risk patient groups, characterized by increased infiltration of the regulatory T cells and M2-like macrophages and fibroblast growth factor (FGF)/FGF receptor signaling activation. Notably, the high-risk patient group demonstrated enhanced sensitivity to immunotherapy, presenting novel therapeutic opportunities. Integrating multi-omics data helped determine the spatial expression pattern of DDIT3 in the tumor microenvironment and its correlation with immune cell infiltration. This multi-dimensional analysis provided a comprehensive understanding of the intricate interplay between DDIT3 and the immune microenvironment in breast cancer. Overall, our study not only facilitates understanding the role of DDIT3 in breast cancer but also offers innovative insights for developing prognostic models and therapeutic strategies. Identifying the DDIT3-related prognostic signature and its association with the immune microenvironment provided a promising avenue for personalized breast cancer treatment.

Keywords:  DDIT3; bioinformatics; biomarker; breast cancer; therapeutic target

DOI:  https://doi.org/10.7150/jca.96491