bims-nurfca 2023-07-23 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–07–23
five papers selected by
Caner Geyik, Istinye University

Modulation of carcinogenesis with selected GRAS nutraceuticals via Keap1-Nrf2 signaling pathway.
KEAP1/NFE2L2 pathway signature outperforms KEAP1/NFE2L2 mutation status and reveals alternative pathway-activating mutations in Non-Small Cell Lung Cancer.
Modulation of NRF2: biological dualism in cancer, targets and possible therapeutic applications.
The Effect of Free and Protein-Bound Maillard Reaction Products N-ε-Carboxymethyllysine, N-ε-Fructosyllysine, and Pyrraline on Nrf2 and NFκB in HCT 116 Cells.
Vanillic acid abrogates cisplatin-induced ovotoxicity through activating Nrf2 pathway.

Phytother Res. 2023 Jul 19.

Modulation of carcinogenesis with selected GRAS nutraceuticals via Keap1-Nrf2 signaling pathway.

Bhagyalakshmi Nair, Jayaprakash K Adithya, Gopika Chandrababu, P K Lakshmi, Joel Joy Koshy, Sreedharan Vilasini Manoj, D B Ambiliraj, Balachandran S Vinod, Gautam Sethi, Lekshmi R Nath.

  Keap1-Nrf2 is a fundamental signaling cascade known to promote or prevent carcinogenesis. Extensive studies identify the key target of modulatory aspects of Keap1-Nrf2 signaling against cancer. Nutraceuticals are those dietary agents with many health benefits that have immense potential for cancer chemoprevention. The nutritional supplements known as nutraceuticals are found to be one of the most promising chemoprevention agents. Upon investigating the dual nature of Nrf2, it became clear that, in addition to shielding normal cells from numerous stresses, Nrf2 may also promote the growth of tumors. In the present review, we performed a systematic analysis of the role of 12 different nutraceuticals like curcumin, sulforaphane, resveratrol, polyunsaturated fatty acids (PUFA) from fish oil, lycopene, soybean, kaempferol, allicin, thymoquinone, quercetin, gingerol, and piperine in modulating the Nrf2/Keap1 signaling mechanism. Among these, 12 Generally Recognized As Safe (GRAS) certified nutraceuticals, sulforaphane is the most extensively studied compound in modulating Keap1-Nrf signaling. Even though there is much evidence at preclinical levels, further high-quality research is still required to validate the potential role of these nutraceuticals in Keap1-Nrf2 modulation.

Keywords:  Keap1 (Kelch-like ECH-associated protein 1); Nrf2 (nuclear factor erythroid 2 [NF-E2] factor 2); cancer; oxidative stress; phytochemicals

DOI:  https://doi.org/10.1002/ptr.7940
J Thorac Oncol. 2023 Jul 18. pii: S1556-0864(23)00684-6. [Epub ahead of print]

KEAP1/NFE2L2 pathway signature outperforms KEAP1/NFE2L2 mutation status and reveals alternative pathway-activating mutations in Non-Small Cell Lung Cancer.

C Arolt, M Dugan, R Wild, V Richartz, B Holz, A H Scheel, J Bragelmann, S Wagener-Ryczek, S Merkelbach-Bruse, J Wolf, R Buettner, L Catanzariti, M Scheffler, A M Hillmer.

   BACKGROUND: Activation of the antioxidant KEAP1/NFE2L2(NRF2)-pathway leads to increased glutamine dependence and an aggressive phenotype in non-small cell lung cancer (NSCLC). Since this pathway has been explored as a clinical target, we developed a transcriptomic signature for identifying KEAP1/NFE2L2-activated tumors.
MATERIAL AND METHODS: A total of 971 NSCLC were used to train an expression signature (K1N2-score) to predict KEAP1/NFE2L2 mutations. 348 in-house NSCLC were analyzed using a NanoString expression panel for validation.
RESULTS: The 46-gene K1N2-score robustly predicted KEAP1/NFE2L2 mutations in the validation set irrespective of histology and mutation (AUC:89.5, sensitivity:90.2%), suggesting that ∼90% of KEAP1/NFE2L2-mutations are pathway-activating. The K1N2-score outperformed KEAP1/NFE2L2 mutational status when predicting patient survival (score p=0.047; mutation p=0.215). In K1N2-score-positive, but KEAP1/NFE2L2wt samples, enrichment testing identified SMARCA4/BRG1 and CUL3 mutations as mimics of KEAP1/NFE2L2 mutations.
CONCLUSIONS: The K1N2-score identified KEAP1/NFE2L2-activated NSCLC by robustly detecting KEAP1/NFE2L2mut cases and discovering alternative genomic activators. It is a potential means for selecting patients with a constitutively active KEAP1/NFE2L2 pathway.

Keywords:  KEAP1; NRF2; NSCLC; lung cancer; transcriptomics

DOI:  https://doi.org/10.1016/j.jtho.2023.07.016
Antioxid Redox Signal. 2023 Jul 20.

Modulation of NRF2: biological dualism in cancer, targets and possible therapeutic applications.

Marialucia Gallorini, Simone Carradori, Emiliano Panieri, Matej Sova, Luciano Saso.

SIGNIFICANCE: The NRF2-KEAP1 system is a master regulator of redox homeostasis and cell adaptation to a variety of exogenous and endogenous stressors. Accumulating evidence from the last decade indicates that the impairment of the redox balance leads to oxidative stress (OS), a common alteration occurring in many human acute and chronic inflammatory diseases,, such as cancer, diabetes, neurodegeneration, and metabolic disorders, and aging.
RECENT ADVANCES: Being located at the intersection of crucial signaling pathways, NRF2 can influence several cellular functions, which extend beyond the maintenance of the redox balance and include cellular metabolism, proteostasis, mitochondrial function and inflammation. For this reason, there is a growing interest in the pharmacologic manipulation of NRF2 for therapeutic purposes, which requires the accurate knowledge of the cell context and the specific time frame both of NRF2 activation and inhibition. This appears to be an important prerequisite and reflects the extreme complexity of the NRF2 signaling, characterized by an intrinsic dualism which mediates beneficial or detrimental effects even in the same biological process.
CRITICAL ISSUES: Of crucial importance will be to understand whether the NRF2 activity modulation might be exploited to exert beneficial outcomes in patients suffering from pathological conditions wherein the OS and the deregulation of inflammatory processes play a crucial role.
FUTURE DIRECTIONS: In this review we discuss the dual involvement of NRF2 in aging, neurodegeneration, metabolic diseases, long-COVID-19 and carcinogenesis and we present an overview of the most recent therapeutic modulators of NRF2, particularly emphasizing on those selected for clinical trials.

DOI: https://doi.org/10.1089/ars.2022.0213
Mol Nutr Food Res. 2023 Jul 19. e2300137

The Effect of Free and Protein-Bound Maillard Reaction Products N-ε-Carboxymethyllysine, N-ε-Fructosyllysine, and Pyrraline on Nrf2 and NFκB in HCT 116 Cells.

Jana Raupbach, Stephan K Müller, Vanessa Schnell, Suse Friedrich, Anne Hellwig, Tilman Grune, Thomas Henle.

   SCOPE: Maillard reaction products (MRPs) are believed to interact with the receptor for advanced glycation endproducts (RAGE) and lead to a pro-inflammatory cellular response. The structural basis for this interaction is scarcely understood. This study investigates the effect of individual lysine modifications in free form or bound to casein on human colon cancer cells.
METHODS AND RESULTS: Selectively glycated casein containing either protein-bound N-ε-carboxymethyllysine (CML), N-ε-fructosyllysine (FL), or pyrraline is prepared and up to 94%, 97%, and 61% of lysine modification could be attributed to CML, FL, or pyrraline, respectively. HCT 116 cells are treated with free CML, pyrraline, FL, or modified casein for 24 h. Native casein is used as control. Intracellular MRP content is analyzed by UPLC-MS/MS. Microscopic analysis of the transcription factors shows no activation of NFκB by free or protein-bound FL or CML, whereas casein containing protein-bound pyrraline activates Nrf2. RAGE expression is not influenced by free or casein-bound MRPs. Activation of Nrf2 by pyrraline-modified casein is confirmed by analyzing Nrf2 target proteins NAD(P)H dehydrogenase (quinone 1) (NQO1) and heme oxygenase-1 (HO-1).
CONCLUSION: Studies on the biological effects of glycated proteins require an individual consideration of defined structures. General statements on the effect of "AGEs" in biological systems are scientifically unsound.

Keywords:  HCT 116 pTRAF; N-ε-carboxymethyllysine; N-ε-fructosyllysine; NFκB; Nrf2; glycation; pyrraline

DOI:  https://doi.org/10.1002/mnfr.202300137
Tissue Cell. 2023 Jul 13. pii: S0040-8166(23)00149-0. [Epub ahead of print]84 102161

Vanillic acid abrogates cisplatin-induced ovotoxicity through activating Nrf2 pathway.

Ahmet Mentese, Selim Demir, Hatice Kucuk, Esin Yulug, Nihal Turkmen Alemdar, Elif Ayazoglu Demir, Yuksel Aliyazicioglu.

  Although cisplatin (CDDP) is an effective anticancer agent, the ovotoxicity that can occur in female patients limits its use. Oxidative stress (OS) and inflammation are known to contribute to CDDP-induced ovotoxicity. Vanillic acid (VA) is a dietary herbal secondary metabolite with high free radical scavenging activity. It was aimed to evaluate the therapeutic effects of VA against CDDP-induced ovotoxicity in rats in this study for the first time. Ovotoxicity was achieved with a single dose of CDDP (5 mg/kg) in female rats. The therapeutic effect of VA was evaluated with 3-day administration of two different doses (5 and 10 mg/kg). While OS, inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers were measured in tissue samples, the levels of reproductive hormones were determined in serum samples using colorimetric methods. The results showed that CDDP-induced nuclear factor erythroid 2-associated factor 2 (Nrf2) inhibition combined with increased OS, inflammation, ERS and apoptosis increased ovarian damage. VA treatments reversed these changes via activating Nrf2 pathway dose-dependently. In addition, histopathological findings also supported the biochemical results. VA may be a good therapeutic molecule candidate for CDDP-induced ovarian damage due to strong antioxidant and Nrf2 activator properties.

Keywords:  Cisplatin; ER stress; Fertility; Inflammation; Nrf2; Oxidative stress; Vanillic acid

DOI:  https://doi.org/10.1016/j.tice.2023.102161