bims-nurfca 2023-10-15 papers

Issue of 2023–10–15
five papers selected by
Caner Geyik, Istinye University

Int J Mol Sci. 2023 Sep 29. pii: 14755. [Epub ahead of print]24(19):

Zinc Finger 521 Modulates the Nrf2-Notch Signaling Pathway in Human Ovarian Carcinoma.

Stefania Scicchitano, Maria Concetta Faniello, Maria Mesuraca.

The human zinc finger protein 521 (ZNF521) is a co-transcriptional factor with multiple recognized regulatory functions in a range of normal, cancer and stem cell compartments. ZNF521 regulates proliferation, progression and CSC (cancer stem cell) compartments in human ovarian cancer (hOC), which is a very aggressive and late-diagnosed female tumor. Two other important regulators of hOC are the NRF2 and NOTCH signaling pathways. In the present paper, the mRNA and protein levels of ZNF521 were correlated with those of the NRF2-NOTCH signaling components in two different hOC cell lines and in a public dataset of 381 hOC patients. The data show that high levels of ZNF521 significantly increase NRF2-NOTCH signaling expression; conversely, the silencing of ZNF521 impairs NRF2-NOTCH signaling. This experimental work shows that, in hOC, different levels of ZNF521 modulate the NRF2-NOTCH signaling pathway and also influences hOC CSC properties.

Keywords: NOTCH; NRF2; ZNF521; human ovarian carcinoma; zinc finger protein

DOI: https://doi.org/10.3390/ijms241914755

Front Oncol. 2023 ;13 1184079

Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers.

Li Lin, Qing Wu, Feifei Lu, Jiaming Lei, Yanhong Zhou, Yifei Liu, Ni Zhu, You Yu, Zhifeng Ning, Tonghui She, Meichun Hu.

Cancer is a borderless global health challenge that continues to threaten human health. Studies have found that oxidative stress (OS) is often associated with the etiology of many diseases, especially the aging process and cancer. Involved in the OS reaction as a key transcription factor, Nrf2 is a pivotal regulator of cellular redox state and detoxification. Nrf2 can prevent oxidative damage by regulating gene expression with antioxidant response elements (ARE) to promote the antioxidant response process. OS is generated with an imbalance in the redox state and promotes the accumulation of mutations and genome instability, thus associated with the establishment and development of different cancers. Nrf2 activation regulates a plethora of processes inducing cellular proliferation, differentiation and death, and is strongly associated with OS-mediated cancer. What's more, Nrf2 activation is also involved in anti-inflammatory effects and metabolic disorders, neurodegenerative diseases, and multidrug resistance. Nrf2 is highly expressed in multiple human body parts of digestive system, respiratory system, reproductive system and nervous system. In oncology research, Nrf2 has emerged as a promising therapeutic target. Therefore, certain natural compounds and drugs can exert anti-cancer effects through the Nrf2 signaling pathway, and blocking the Nrf2 signaling pathway can reduce some types of tumor recurrence rates and increase sensitivity to chemotherapy. However, Nrf2's dual role and controversial impact in cancer are inevitable consideration factors when treating Nrf2 as a therapeutic target. In this review, we summarized the current state of biological characteristics of Nrf2 and its dual role and development mechanism in different tumor cells, discussed Keap1/Nrf2/ARE signaling pathway and its downstream genes, elaborated the expression of related signaling pathways such as AMPK/mTOR and NF-κB. Besides, the main mechanism of Nrf2 as a cancer therapeutic target and the therapeutic strategies using Nrf2 inhibitors or activators, as well as the possible positive and negative effects of Nrf2 activation were also reviewed. It can be concluded that Nrf2 is related to OS and serves as an important factor in cancer formation and development, thus provides a basis for targeted therapy in human cancers.

Keywords: Nrf2; Nrf2 signaling pathway; cancer; oxidative stress; therapeutic target

DOI: https://doi.org/10.3389/fonc.2023.1184079

Med Princ Pract. 2023 Oct 12.

Prognostic Worth of Nrf2/BACH1/HO-1 Protein Expression in the Development of Breast Cancer.

Precious Barnes, Elvis Agbo, Jianjie Wang, Benjamin Amoani, Yeboah Kwaku Opoku, Perditer Okyere, Roland Osei Saahene.

OBJECTIVES: Nrf2/ BACH1/ HO-1 proteins have been implicated in the development and progression of tumors. However, their clinical relevance in breast cancer remains unclear and understudied. This study evaluated Nrf2/ BACH1/ HO-1 protein expression and its relationship with age, tumor grade, tumor stage and TNM, ER, PR, HER2 and histologic type.
METHODS: 114 female breast cancer and 30 non-cancerous tissues were evaluated for Nrf2/ BACH1/ HO-1 protein expression using immunohistochemistry and Western blot. The relationships between the expression and clinicopathologic factors were assessed using the Chi-square test.
RESULTS: 74% of the cancerous samples had high Nrf2 protein expression and 26% of them had low Nrf2 protein expression. Regarding the non-cancer samples 43% had high Nrf2 protein expression and 57% had low Nrf2 protein expression (p < 0.002). 39% of the cancerous samples had high BACH1 protein expression and 61% had low BACH1 protein expression. For the non-cancer samples 80% had high BACH1 protein expression and 20% had low BACH1 protein expression (p < 0.031). 67% of the cancerous samples had high HO-1 protein expression and 33% had low HO-1 protein expression. However, for the non-cancer samples 17% of them had high HO-1 protein expression and 83% had low HO-1 protein expression (p < 0.001). The expression of Nrf2 and HO-1 significantly correlated with tumor grade whilst BACH1 was significantly associated with tumor stage (p < 0.05).
CONCLUSION: Nrf2, BACH1 and HO-1 could be explored as a biomarker for cancer stage, progression, and prognosis.

DOI: https://doi.org/10.1159/000534534

Inflammation. 2023 Oct 14.

The Role of Nrf2 and Inflammation on the Dissimilar Cardiotoxicity of Doxorubicin in Two-Time Points: a Cardio-Oncology In Vivo Study Through Time.

Ana Reis-Mendes, Mariana Ferreira, Ana Isabel Padrão, José Alberto Duarte, Margarida Duarte-Araújo, Fernando Remião, Félix Carvalho, Emília Sousa, Maria Lourdes Bastos, Vera Marisa Costa.

Doxorubicin (DOX) is a topoisomerase II inhibitor used in cancer therapy. Despite its efficacy, DOX causes serious adverse effects, such as short- and long-term cardiotoxicity. This work aimed to assess the short- and long-term cardiotoxicity of DOX and the role of inflammation and antioxidant defenses on that cardiotoxicity in a mice model. Adult CD-1 male mice received a cumulative dose of 9.0 mg/kg of DOX (2 biweekly intraperitoneal injections (ip), for 3 weeks). One week (1W) or 5 months (5M) after the last DOX administration, the heart was collected. One week after DOX, a significant increase in p62, tumor necrosis factor receptor (TNFR) 2, glutathione peroxidase 1, catalase, inducible nitric oxide synthase (iNOS) cardiac expression, and a trend towards an increase in interleukin (IL)-6, TNFR1, and B-cell lymphoma 2 associated X (Bax) expression was observed. Moreover, DOX induced a decrease on nuclear factor erythroid-2 related factor 2 (Nrf2) cardiac expression. In both 1W and 5M, DOX led to a high density of infiltrating M1 macrophages, but only the 1W-DOX group had a significantly higher number of nuclear factor κB (NF-κB) p65 immunopositive cells. As late effects (5M), an increase in Nrf2, myeloperoxidase, IL-33, tumor necrosis factor-α (TNF-α), superoxide dismutase 2 (SOD2) expression, and a trend towards increased catalase expression were observed. Moreover, B-cell lymphoma 2 (Bcl-2), cyclooxygenase-2 (COX-2), and carbonylated proteins expression decreased, and a trend towards decreased p38 mitogen-activated protein kinase (MAPK) expression were seen. Our study demonstrated that DOX induces adverse outcome pathways related to inflammation and oxidative stress, although activating different time-dependent response mechanisms.

Keywords: Nrf2.; cardiotoxicity; doxorubicin; inflammation; long-term effects; redox homeostasis disruption

DOI: https://doi.org/10.1007/s10753-023-01908-0

Chem Sci. 2023 Oct 11. 14(39): 10800-10805

A cell-active cyclic peptide targeting the Nrf2/Keap1 protein-protein interaction.

Jessica Iegre, Sona Krajcovicova, Anders Gunnarsson, Lisa Wissler, Helena Käck, Anna Luchniak, Stefan Tångefjord, Frank Narjes, David R Spring.

The disruption of the protein-protein interaction (PPI) between Nrf2 and Keap1 is an attractive strategy to counteract the oxidative stress that characterises a variety of severe diseases. Peptides represent a complementary approach to small molecules for the inhibition of this therapeutically important PPI. However, due to their polar nature and the negative net charge required for binding to Keap1, the peptides reported to date exhibit either mid-micromolar activity or are inactive in cells. Herein, we present a two-component peptide stapling strategy to rapidly access a variety of constrained and functionalised peptides that target the Nrf2/Keap1 PPI. The most promising peptide, P8-H containing a fatty acid tag, binds to Keap1 with nanomolar affinity and is effective at inducing transcription of ARE genes in a human lung epithelial cell line at sub-micromolar concentration. Furthermore, crystallography of the peptide in complex with Keap1 yielded a high resolution X-ray structure, adding to the toolbox of structures available to develop cell-permeable peptidomimetic inhibitors.

DOI: https://doi.org/10.1039/d3sc04083f