bims-nurfca 2022-11-20 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2022–11–20
eight papers selected by
Caner Geyik, Istinye University

Docosahexaenoic Acid Reverses Epithelial-Mesenchymal Transition and Drug Resistance by Impairing the PI3K/AKT/ Nrf2/GPX4 Signalling Pathway in Docetaxel-Resistant PC3 Prostate Cancer Cells.
Nuclear factor erythroid-2-related factor 2 (Nrf2) is a potential prognostic factor in patients with gastric adenocarcinoma.
Regulation mechanism of ferroptosis and its research progress in tumor immunotherapy.
Evaluation of the mycotoxin patulin on cytotoxicity and oxidative stress in human glioblastoma cells and investigation of protective effect of the antioxidant N-acetylcysteine (NAC).
Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy.
The ERα-NRF2 signalling axis promotes bicalutamide resistance in prostate cancer.
Trabectedin induces ferroptosis via regulation of HIF-1α/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells.
A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1β and IL-6.

Folia Biol (Praha). 2022 ;68(2): 59-71

Docosahexaenoic Acid Reverses Epithelial-Mesenchymal Transition and Drug Resistance by Impairing the PI3K/AKT/ Nrf2/GPX4 Signalling Pathway in Docetaxel-Resistant PC3 Prostate Cancer Cells.

Z C Shao, B H Zhu, A F Huang, M Q Su, L J An, Z P Wu, Y J Jiang, H Guo, X-Q Han, C-M Liu.

Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase- 3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT /Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.
Arab J Gastroenterol. 2022 Nov 15. pii: S1687-1979(22)00088-0. [Epub ahead of print]

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a potential prognostic factor in patients with gastric adenocarcinoma.

Hüseyin Alakuş, Mustafa Kaya, Hatice Özer, Hatice Reyhan Eğilmez, Kürşat Karadayı.

   BACKGROUND: Gastric cancer is one of the leading causes of cancer-related death, and many researchers are focused on the discovery and use of different biomarkers in prognosis prediction. The use of Nrf2 as a prognostic marker in patients with gastric cancer remains controversial. In this study, we evaluated the expression of Nrf2 protein in gastric adenocarcinoma.
PATIENTS AND METHODS: A total of 86 patients who underwent gastric resection and D2 lymph node dissection due to gastric adenocarcinoma were included. Clinicopathological characteristics, such as age, gender, gastrectomy type, pathologic T (pT) and N (pN) stages, tumor grade, tumor type per Lauren's classification, presence of lymphovascular invasion, and Nrf2 expression were evaluated.
RESULTS: While pT, pN, and Nrf-2 expression were found to be negative prognostic predictors for overall survival in one-way analysis of variance, Nrf-2 expression was the only significant negative prognostic predictor in multivariance analysis. pT, pN, diffuse type, high tumor grade, and Nrf-2 expression significantly affected overall survival in Kaplan-Meier survival analyses (p = 0.02, p = 0.03, p < 0.01, p = 0.027, and p = 0.001, respectively).
CONCLUSIONS: Our findings support that Nrf2 is a prognostic marker in patients with gastric adenocarcinoma. Anti-Nrf2 therapy options should be investigated to improve prognosis in gastric cancer patients.

Keywords:  Adenocarcinoma; Gastrectomy; NF-E2-related factor 2; Prognosis; Stomach neoplasms

DOI:  https://doi.org/10.1016/j.ajg.2022.10.010
Front Mol Biosci. 2022 ;9 1045548

Regulation mechanism of ferroptosis and its research progress in tumor immunotherapy.

Jing Xu, Xiaolin Lin, Ting Han, Qingqing Zhou, Yang Su, Shuqing Jiang, Xiuying Xiao, Tengfei Liu.

  Ferroptosis is a novel regulatory cell death, which is characterized by iron dependency and mainly caused by accumulation of intracellular lipid peroxides and reactive oxygen species. Ferroptosis plays an important role in the occurrence and development of a variety of malignant tumors, especially in anti-tumor treatment. As an emerging treatment method, the immunotherapy has been widely applied in the clinical practice, and the role of ferroptosis in tumor immunotherapy has been gradually explored. This study aims to illustrate the features of ferroptosis, and its role in anti-tumor immunotherapy and potential clinical application.

Keywords:  anti-tumor immunotherapy; ferroptosis; ferroptosis inducer and inhibitor; metabolic pathway; review

DOI:  https://doi.org/10.3389/fmolb.2022.1045548
Toxicon. 2022 Oct 27. pii: S0041-0101(22)00308-7. [Epub ahead of print]221 106957

Evaluation of the mycotoxin patulin on cytotoxicity and oxidative stress in human glioblastoma cells and investigation of protective effect of the antioxidant N-acetylcysteine (NAC).

Shu-Shong Hsu, Yung-Shang Lin, Li-Min Chio, Wei-Zhe Liang.

  Mycotoxins are secondary metabolites produced by various kinds of fungi that can induce disease in humans. The fungal species Penicillium expansum produces patulin (C7H6O4), a polyketide lactone mycotoxin found in fruits. Patulin is classified as noncarcinogen; however, recently, it has been associated with harmful effects on the central nervous system. Patulin's toxic action has been established in various brain models; however, its effect on human glioblastoma remains elusive. This study explores whether patulin induces cytotoxicity through oxidative stress in DBTRG-05MG human glioblastoma cells. This study also evaluates whether the antioxidant N-acetylcysteine (NAC) protects against patulin-induced cytotoxicity. In DBTRG-05MG cells, patulin concentration (10-60 μM) dependently induced cytotoxicity. Concerning oxidative stress, patulin (10 and 20 μM) increased the production of intracellular reactive oxygen species (ROS) but depleted reduced glutathione (GSH) contents and regulated the expressions of antioxidant-related proteins (Nrf2 and HO-1). Furthermore, patulin induced cytotoxicity via modulation of apoptosis-related protein expressions (Bax, cleaved caspase-9, and cleaved caspase-3). These cytotoxic responses were partially reversed via pretreatment with NAC (10 μM). In summary, these data help us understand the toxicology of patulin in human glioblastoma and evaluate whether NAC could clinically reduce patulin-affected brain damage.

Keywords:  Antioxidant; Apoptosis; Human glioblastoma cells; Oxidative stress; Patulin; ROS

DOI:  https://doi.org/10.1016/j.toxicon.2022.106957
Acta Pharm Sin B. 2022 Nov;12(11): 4224-4234

Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy.

Zekun Li, Yongchun Pan, Shiyu Du, Yayao Li, Chao Chen, Hongxiu Song, Yueyao Wu, Xiaowei Luan, Qin Xu, Xiaoxiang Guan, Yujun Song, Xin Han.

  Near-infrared (NIR)-light-triggered nanomedicine, including photodynamic therapy (PDT) and photothermal therapy (PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania (TiO2-x ) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase (HAase) and glutathione (GSH) can readily destroy hyaluronic acid (HA) and disulfide bond and releases the Cas9/sgRNA from TiO2-x to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2 (NRF2) and heat shock protein 90α (HSP90α), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO2-x demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.

Keywords:  Gene editing; Heat shock protein 90α; Nanoprodrug; Near-infrared phototherapy; Nuclear factor E2-related factor 2; Sensitized phototherapy; TiO2-x; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.apsb.2022.06.016
Cell Commun Signal. 2022 Nov 14. 20(1): 178

The ERα-NRF2 signalling axis promotes bicalutamide resistance in prostate cancer.

Lei Tian, Yanfei Peng, Kuo Yang, Jiasong Cao, Xiaoling Du, Zhixian Liang, Jiandang Shi, Ju Zhang.

   BACKGROUND: Bicalutamide is a nonsteroidal antiandrogen widely used as a first-line clinical treatment for advanced prostate cancer (PCa). Although patients initially show effective responses to bicalutamide treatment, resistance to bicalutamide frequently occurs and leads to the development of castration-resistant PCa (CRPC). This research investigated the roles of the oestrogen receptor α (ERα)-nuclear factor E2-related factor 2 (NRF2) signalling pathway in bicalutamide resistance in PCa cells.
METHODS: We performed bioinformatic analysis and immunohistochemical staining on normal and cancerous prostate tissue to evaluate ERα and NRF2 expression and their correlation. Gene expression and localization in PCa cell lines were further investigated using real-time reverse transcription PCR/Western blotting and immunofluorescence staining. We treated PCa cells with the ER inhibitor tamoxifen and performed luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays to understand ERα-dependent NRF2 expression. Overexpression and knockdown of ERα and NRF2 were used to explore the potential role of the ERα-NRF2 signalling axis in bicalutamide resistance in PCa cells.
RESULTS: We found that the expression of ERα and NRF2 was positively correlated and was higher in human CRPC tissues than in primary PCa tissues. Treatment with oestrogen or bicalutamide increased the expression of ERα and NRF2 as well as NRF2 target genes in PCa cell lines. These effects were blocked by pretreatment with tamoxifen. ChIP assays demonstrated that ERα directly binds to the oestrogen response element (ERE) in the NRF2 promoter. This binding led to increased transcriptional activity of NRF2 in a luciferase reporter assay. Activation of the ERα-NRF2 signalling axis increased the expression of bicalutamide resistance-related genes. Inhibition of this signalling axis by knockdown of ERα or NRF2 downregulated the expression of bicalutamide resistance-related genes and inhibited the proliferation and migration of PCa cells.
CONCLUSIONS: We demonstrated the transcriptional interaction between ERα and NRF2 in CRPC tissues and cell lines by showing the direct binding of ERα to the ERE in the NRF2 promoter under oestrogen treatment. Activation of the ERα-NRF2 signalling axis contributes to bicalutamide resistance in PCa cells, suggesting that the ERα-NRF2 signalling axis is a potential therapeutic target for CRPC. Video Abstract.

Keywords:  Bicalutamide; Castration-resistant; ERα; NRF2; PCa

DOI:  https://doi.org/10.1186/s12964-022-00979-0
Chem Biol Interact. 2022 Nov 14. pii: S0009-2797(22)00467-7. [Epub ahead of print] 110262

Trabectedin induces ferroptosis via regulation of HIF-1α/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells.

Shunv Cai, Zewu Ding, Xinyi Liu, Jian Zeng.

   BACKGROUND AND OBJECTIVES: Non-small cell lung cancer (NSCLC) is a global health concern. NSCLC treatment outcomes are generally poor due to treatment resistance or toxicity. Ferroptosis is a novel cell death triggered by iron accumulation, reactive oxygen species (ROS), and lipid peroxidation. Ferroptosis may kill cancer cells, particularly those resistant to apoptosis.
MATERIALS AND METHODS: The Cell Counting Kit-8 assay assessed NSCLC cell viability after trabectedin treatment. Flow cytometry with Annexin V-FITC staining evaluated cell death. ROS, iron, lipid peroxidation, and GSH levels were measured using commercial kits. qRT-PCR and western blots evaluated messenger RNA and protein levels. Proteins were inhibited using short interfering RNA transfection and specific inhibitors.
RESULTS: Trabectedin was cytotoxic to NSCLC cells regardless of p53 status. Trabectedin upregulated iron, ROS, and lipid peroxidation in NSCLC cells, causing ferroptosis. Trabectedin increases iron and ROS levels by upregulating transferrin receptor 1 and the HIF-1/IRP1 axis. In NSCLC cells, trabectedin suppresses glutathione peroxidase 4, followed by the Keap1/Nrf2 axis.
CONCLUSIONS: Our findings imply that trabectedin may treat NSCLC effectively.

Keywords:  Ferroptosis; GPX4; Non-small cell lung cancer; TFR1; Trabectedin

DOI:  https://doi.org/10.1016/j.cbi.2022.110262
Acta Pharm Sin B. 2022 Nov;12(11): 4180-4192

A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1β and IL-6.

Liping Liao, Wenzhen Dang, Tingting Lin, Jinghua Yu, Tonghai Liu, Wen Li, Senhao Xiao, Lei Feng, Jing Huang, Rong Fu, Jiacheng Li, Liping Liu, Mingchen Wang, Hongru Tao, Hualiang Jiang, Kaixian Chen, Xingxing Diao, Bing Zhou, Xiaoyan Shen, Cheng Luo.

  Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATP-competitive inhibitor of PGK1 with an affinity of K d = 99.08 nmol/L. DC-PGKI stabilizes PGK1 in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition, DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages. Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium (DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.

Keywords:  Glycolysis; Inflammation; Macrophages; NRF2; Phosphoglycerate kinase1

DOI:  https://doi.org/10.1016/j.apsb.2022.05.012