bims-nurfca 2024-07-07 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024–07–07
seven papers selected by
Caner Geyik, Istinye University

The interplay between microRNAs and Nrf2 signaling in human cancers.
Cyclopeptide RA-V from Rubia yunnanensis restores activity of Adagrasib against colorectal cancer by reducing the expression of Nrf2.
Mutant Nrf2E79Q enhances the promotion and progression of a subset of oncogenic Ras keratinocytes and skin tumors.
Association Between Genes in the Nuclear Factor E2-Related Factor 2 Antioxidative Response Elements Pathway and Cancer-Related Fatigue in Women With Early-Stage Breast Cancer.
Neutrophil in the suppressed immune microenvironment: Critical prognostic factor for lung adenocarcinoma patients with KEAP1 mutation.
Low-dose dimethylfumarate attenuates colitis-associated cancer in mice through M2 macrophage polarization and blocking oxidative stress.
A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools.

Cancer Cell Int. 2024 Jul 05. 24(1): 234

The interplay between microRNAs and Nrf2 signaling in human cancers.

Reza Panahizadeh, Mohammad Amin Vatankhah, Ali Safari, Hesam Danesh, Negin Nazmi, Pourya Gholizadeh, Narges Soozangar, Farhad Jeddi.

  MicroRNAs (miRNAs), as a class of nonprotein-coding RNAs, post-transcriptionally regulate the expression of target genes by base pairing to 3'-untranslated regions (3'-UTRs). Nuclear factor E2-related factor 2 (Nrf2) has been identified as a critical component of the antioxidant defense mechanism. Dysregulation is associated with chemoresistance and radioresistance in cancerous cells. MiRNA-mediated regulation of the Nrf2 signaling pathway has been shown to have important implications for the development of various cancers. In this article, we review the roles of miRNAs as regulators of the Nrf2 pathway in different human cancers. Ras-associated binding (Rab) proteins have an essential role regulation of vesicle transport, as well as oncogenic functions in preventing chemotherapy efficacy and cancer development. More importantly, increased evidence indicated that the interaction between miRNAs and Rabs has been determined to play critical roles in cancer therapy. However, the significant limitations in using miRNAs for therapeutic applications include cross-targeting and instability of miRNAs. The detailed aspect of the interaction of miRNAs and Rabs is not clearly understood. In the current review, we highlighted the involvement of these molecules as regulators of the Nrf2 pathway in cancer pathogenesis. Potential methods and several obstacles in developing miRNAs as an anticancer therapy are also mentioned.

Keywords:  Cancer; Keap1; Nrf2; miRNAs

DOI:  https://doi.org/10.1186/s12935-024-03430-1
Pharmacol Res. 2024 Jun 28. pii: S1043-6618(24)00197-X. [Epub ahead of print] 107252

Cyclopeptide RA-V from Rubia yunnanensis restores activity of Adagrasib against colorectal cancer by reducing the expression of Nrf2.

Jiang Zhuangzhuang, Ye Shuqing, Wu Yingwei, Zhou Chen, Cao Feng, Tan Ninghua.

  Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) harboring KRAS-activating mutations. However, emergence of the acquired resistance limits its long-term efficacy and clinical application. Further understanding of the mechanism of the acquired resistance is crucial for developing more new effective therapeutic strategies. Herein, we firstly found a new connection between the acquired resistance to MRTX849 and nuclear factor erythroid 2-related factor 2 (Nrf2). The expression levels of Nrf2 and GLS1 proteins were substantially elevated in different CRC cell lines with the acquired resistance to MRTX849 in comparison with their corresponding parental cell lines. Next, we discovered that RA-V, one of natural cyclopeptides isolated from the roots of Rubia yunnanensis, could restore the response of resistant CRC cells to MRTX849. The results of molecular mechanisms showed that RA-V suppressed Nrf2 protein through the ubiquitin-proteasome-dependent degradation, leading to the induction of oxidative and ER stress, and DNA damage in CRC cell lines. Consequently, RA-V reverses the resistance to MRTX849 by inhibiting the Nrf2/GLS1 axis, which shows the potential for further developing into one of novel adjuvant therapies of MRTX849.

Keywords:  Bafilomycin A1 (PubChem CID: 6436223); CHX (PubChem CID: 6197); Colorectal cancer; DAPI (PubChem CID: 2954); DMSO (PubChem CID: 679); DNA damage; Leupeptin (PubChem CID: 72429); MG132 (PubChem CID: 462382); MRTX849 (PubChem CID: 138611145); MRTX849 resistance; MTT (PubChem CID: 64965); Natural cyclopeptide RA-V; Nrf2/GLS1 axis; Oxidative and ER stress; RA-V (PubChem CID: 13361282); tBHQ (PubChem CID: 16043)

DOI:  https://doi.org/10.1016/j.phrs.2024.107252
Redox Biol. 2024 Jun 28. pii: S2213-2317(24)00239-8. [Epub ahead of print]75 103261

Mutant Nrf2E79Q enhances the promotion and progression of a subset of oncogenic Ras keratinocytes and skin tumors.

John G Witherspoon, Jonathan R Hall, Dereje Jima, Hannah M Atkins, Nathan T Wamsley, Michael B Major, Bernard E Weissman, Robert C Smart.

  Squamous cell carcinomas (SCCs), including lung, head & neck, bladder, and skin SCCs often display constitutive activation of the KEAP1-NRF2 pathway. Constitutive activation is achieved through multiple mechanisms, including activating mutations in NFE2L2 (NRF2). To determine the functional consequences of Nrf2 activation on skin SCC development, we assessed the effects of mutant Nrf2E79Q expression, one of the most common activating mutations in human SCCs, on tumor promotion and progression in the mouse skin multistage carcinogenesis model using a DMBA-initiation/TPA-promotion protocol where the Hras A->T mutation (Q61L) is the canonical driver mutation. Nrf2E79Q expression was temporally and conditionally activated in the epidermis at two stages of tumor development: 1) after DMBA initiation in the epidermis but before cutaneous tumor development and 2) in pre-existing DMBA-initiated/TPA-promoted squamous papillomas. Expression of Nrf2E79Q in the epidermis after DMBA initiation but before tumor occurrence inhibited the development/promotion of 70% of squamous papillomas. However, the remaining papillomas often displayed non-canonical Hras and Kras mutations and enhanced progression to SCCs compared to control mice expressing wildtype Nrf2. Nrf2E79Q expression in pre-existing tumors caused rapid regression of 60% of papillomas. The remaining papillomas displayed the expected canonical Hras A->T mutation (Q61L) and enhanced progression to SCCs. These results demonstrate that mutant Nrf2E79Q enhances the promotion and progression of a subset of skin tumors and alters the frequency and diversity of oncogenic Ras mutations when expressed early after initiation.

Keywords:  Cancer; Conversion; KEAP1; Mouse skin multistage carcinogenesis model; NFE2L2; Nrf2; Papilloma; Progression; Promotion; Proteomics; RNAseq; Ras; Squamous cell carcinoma

DOI:  https://doi.org/10.1016/j.redox.2024.103261
Oncol Nurs Forum. 2024 Jun 14. 51(4): 404-416

Association Between Genes in the Nuclear Factor E2-Related Factor 2 Antioxidative Response Elements Pathway and Cancer-Related Fatigue in Women With Early-Stage Breast Cancer.

Tara S Davis, Theresa A Koleck, Margaret Q Rosenzweig, Christine Miaskowski, Kirk I Erickson, Susan M Sereika, Catherine M Bender, Yvette P Conley.

   OBJECTIVES: To explore genes in the nuclear factor E2-related factor 2 antioxidative response elements (Nrf2-ARE) signaling pathway using a multiomics approach for associations with variability of cancer-related fatigue (CRF) in postmenopausal women with early-stage hormone receptor-positive breast cancer.
SAMPLE &AMP; SETTING: Postmenopausal women (N = 116) with early-stage hormone receptor-positive breast cancer were recruited from western Pennsylvania.
METHODS &AMP; VARIABLES: Candidate genes from the Nrf2-ARE pathway were investigated for associations with CRF occurrence and severity. Associations were evaluated using logistic regression for occurrence and linear regression for severity.
RESULTS: The rs2706110 TT genotype in NFE2L2 was associated with a 3.5-fold increase in odds of CRF occurrence. The cytosine-phosphate-guanine (CpG) site cg22820568 in PRDX1 was associated with CRF occurrence and severity.
IMPLICATIONS FOR NURSING: Biomarkers based on Nrf2-ARE genes may help to identify women at increased risk for more severe CRF and to develop targeted interventions.

Keywords:  DNA methylation; antioxidants; breast neoplasms; fatigue; polymorphism

DOI:  https://doi.org/10.1188/24.ONF.404-416
Front Genet. 2024 ;15 1382421

Neutrophil in the suppressed immune microenvironment: Critical prognostic factor for lung adenocarcinoma patients with KEAP1 mutation.

Zhongzhao Wang, Haojue Wang, Mingjia Liu, Xinhang Ning, Yang Chen, Hao Tang.

   Purpose: It is still unclear whether KEAP1 mutation is detrimental to immunotherapy of lung adenocarcinoma (LUAD) patients, we try to analyse the exact changes in the TME in LUAD patients with KEAP1 mutations and to identify key factors influencing prognosis.
Experimental design: A total of 1,029 patients with lung squamous carcinoma (LUSC) or LUAD with data obtained from The Cancer Genome Atlas were included in this study. The TME and OS of patients with LUAD stratified by mutant versus wild-type KEAP1 status were comprehensively measured. Moreover, we classified LUAD patients with KEAP1 mutations into three subtypes, by unsupervised consensus clustering. We further analysed the TME, OS, commutated genes and metabolic pathways of different subgroups. A total of 40 LUAD patients underwent immunotherapy were collected and classified into mutant KEAP1 group and wild-type KEAP1 group. We also conducted immunohistochemical staining in KEAP1-MT groups.
Result: Suppressed TME was observed not only in LUAD patients but also in LUSC patients. LUAD patients with mutant KEAP1 underwent immunotherapy had worse PFS than wild-type KEAP1. Unsupervised consensus clustering analysis suggested that the three subtypes of patients exhibited different densities of neutrophil infiltration and had different OS results: cluster 2 patients had significantly higher levels of neutrophils had significantly worse prognoses than those of patients in clusters 1 and 3 and patients with wild-type KEAP1. Univariate and multivariate Cox analyses proved that a high density of neutrophils was significantly associated with worse OS and immunohistochemical staining proved that shorter PFS showed high density of neutrophils.
Conclusion: KEAP1 mutation significantly suppresses the tumour immune microenvironment in LUAD patients. LUAD patients with mutant KEAP1 underwent immunotherapy had worse PFS than with wild-type KEAP1. Neutrophils may play an important role in the prognosis of LUAD patients with KEAP1 mutations and may provide a promising therapeutic target.

Keywords:  KEAP1; NSCLC; lung adenocarcinoma; neutrophil; tumour microenvironment

DOI:  https://doi.org/10.3389/fgene.2024.1382421
Toxicol Appl Pharmacol. 2024 Jun 28. pii: S0041-008X(24)00216-3. [Epub ahead of print]489 117018

Low-dose dimethylfumarate attenuates colitis-associated cancer in mice through M2 macrophage polarization and blocking oxidative stress.

Ismahane Abdelaziz, Abdelkader Bounaama, Bahia Djerdjouri, Zine-Charaf Amir-Tidadini.

  Colitis-associated cancer (CAC) is an aggressive subtype of colorectal cancer that can develop in ulcerative colitis patients and is driven by chronic inflammation and oxidative stress. Current chemotherapy for CAC, based on 5-fluorouracil and oxalipltin, is not fully effective and displays severe side effects, prompting the search for alternative therapies. Dimethylfumarate (DMF), an activator of the nuclear factor erythroid 2-related factor 2 (NRF2), is a potent antioxidant and immunomodelatrory drug used in the treatment of multiple sclerosis and showed a strong anti-inflammatory effect on experimental colitis. Here, we investigated the chemotherapeutic effect of DMF on an experimental model of CAC. Male NMRI mice were given two subcutaneous injections of 1,2 Dimethylhydrazine (DMH), followed by three cycles of dextran sulfate sodium (DSS). Low-dose (DMF30) and high-dose of DMF (DMF100) or oxaliplatin (OXA) were administered from the 8th to 12th week of the experiment, and then the colon tissues were analysed histologically and biochemically. DMH/DSS induced dysplastic aberrant crypt foci (ACF), oxidative stress, and severe colonic inflammation, with a predominance of pro-inflammatory M1 macrophages. As OXA, DMF30 reduced ACF multiplicity and crypt dysplasia, but further restored redox status, and reduced colitis severity by shifting macrophages towards the anti-inflammatory M2 phenotype. Surprisingly, DMF100 exacerbated ACF multiplicity, oxidative stress, and colon inflammation, likely through NRF2 and p53 overexpression in colonic inflammatory cells. DMF had a dual effect on CAC. At low dose, DMF is chemotherapeutic and acts as an antioxidant and immunomodulator, whereas at high dose, DMF is pro-oxidant and exacerbates colitis-associated cancer.

Keywords:  Colitis-associated cancer; Dimethylfumarate; Macrophage polarization; NRF2; Oxidative stress; p53

DOI:  https://doi.org/10.1016/j.taap.2024.117018
Proc Natl Acad Sci U S A. 2024 Jul 09. 121(28): e2401579121

A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools.

Aidan T Pezacki, Ryan L Gonciarz, Toshitaka Okamura, Carson D Matier, Laura Torrente, Ke Cheng, Sophia G Miller, Martina Ralle, Nathan P Ward, Gina M DeNicola, Adam R Renslo, Christopher J Chang.

  Iron is an essential element for life owing to its ability to participate in a diverse array of oxidation-reduction reactions. However, misregulation of iron-dependent redox cycling can also produce oxidative stress, contributing to cell growth, proliferation, and death pathways underlying aging, cancer, neurodegeneration, and metabolic diseases. Fluorescent probes that selectively monitor loosely bound Fe(II) ions, termed the labile iron pool, are potentially powerful tools for studies of this metal nutrient; however, the dynamic spatiotemporal nature and potent fluorescence quenching capacity of these bioavailable metal stores pose challenges for their detection. Here, we report a tandem activity-based sensing and labeling strategy that enables imaging of labile iron pools in live cells through enhancement in cellular retention. Iron green-1 fluoromethyl (IG1-FM) reacts selectively with Fe(II) using an endoperoxide trigger to release a quinone methide dye for subsequent attachment to proximal biological nucleophiles, providing a permanent fluorescent stain at sites of elevated labile iron. IG1-FM imaging reveals that degradation of the major iron storage protein ferritin through ferritinophagy expands the labile iron pool, while activation of nuclear factor-erythroid 2-related factor 2 (NRF2) antioxidant response elements (AREs) depletes it. We further show that lung cancer cells with heightened NRF2 activation, and thus lower basal labile iron, have reduced viability when treated with an iron chelator. By connecting labile iron pools and NRF2-ARE activity to a druggable metal-dependent vulnerability in cancer, this work provides a starting point for broader investigations into the roles of transition metal and antioxidant signaling pathways in health and disease.

Keywords:  activity-based sensing; antioxidant regulation; cancer metabolism; fluorescent iron probe; transition metal signaling

DOI:  https://doi.org/10.1073/pnas.2401579121