bims-nurfca 2023-10-01 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–10–01
eight papers selected by
Caner Geyik, Istinye University

NRF2 Suppression Enhances the Susceptibility of Pancreatic Cancer Cells, Miapaca-2 to Paclitaxel.
Inhibition of LNC EBLN3P Enhances Radiation-Induced Mitochondrial Damage in Lung Cancer Cells by Targeting the Keap1/Nrf2/HO-1 Axis.
Brusatol induces ferroptosis in oesophageal squamous cell carcinoma by repressing GSH synthesis and increasing the labile iron pool via inhibition of the NRF2 pathway.
Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer.
Redox Regulation of Nrf2 in Cisplatin-Induced Kidney Injury.
NRF2, a Superstar of Ferroptosis.
Expression of Ferroptosis-Related Proteins Glutathione Peroxidase 4, Nuclear Factor Erythroid 2-Related Factor 2, and Solute Carrier Family 7 Member 11 in Gastric Cancer Patients.
FGF2 Rescued Cisplatin-Injured Granulosa Cells through the NRF2-Autophagy Pathway.

Mol Biotechnol. 2023 Sep 23.

NRF2 Suppression Enhances the Susceptibility of Pancreatic Cancer Cells, Miapaca-2 to Paclitaxel.

Negin Riazi-Tabrizi, Mohammad Khalaj-Kondori, Sahar Safaei, Mohammad Amini, Hamidreza Hassanian, Mohadeseh Maghsoudi, Shima Hasani, Behzad Baradaran.

  Pancreatic cancer is one of the most deadly diseases, with a very high metastasis and low survival rate. High levels of NRF2 have been detected in numerous malignancies, including head, neck, lung, and colon cancers, promoting the expansion and survival of cancer cells and chemical resistance to stressful conditions and affecting the response to treatment. To evaluate the possibility that modulation of NRF2 expression could be effective in treating pancreatic cancer cells, we explored the effect of knockdown of the NRF2 gene by NRF2-specific siRNA and its influence in combination with paclitaxel on pancreatic cancer cells. Miapaca-2 cell line, due to the high expression of the NRF2 gene, was selected for this study. Then, Miapaca-2 cells in different groups were treated with NRF2 siRNA and paclitaxel separately and in combination. After that, cell viability was measured by MTT assay and apoptosis induction by Annexin V-FITC/PI staining test. Cell cycle and autophagy were examined by flow cytometry, and cell migration was assessed by wound-healing assay. Finally, the expression of genes involved in apoptosis, Bax, Caspase-3, Caspase-9, and genes related to migration pathway, MMP-2, and MMP-9 in different groups were measured using qRT-PCR. Combined use of NRF2-specific siRNA with paclitaxel significantly reduced NRF2 gene expression in pancreatic cancer cells. NRF2 siRNA transfection significantly reduced cell viability. In addition, paclitaxel combination therapy with NRF2 siRNA strengthens the anti-tumor effects, such as inhibiting cell migration and provoking apoptosis, and autophagy and the cell cycle arrest in the G2 phase. NRF2 suppression augmented the expression of Bax, Caspase-3, and Caspase-9 genes and lowered the expression of Bcl-2, MMP-2, and MMP-9 genes, which play crucial roles in the pathways of apoptosis and cell migration, respectively. NRF2 siRNA enhances the susceptibility of Miapaca-2 cells to paclitaxel in pancreatic cancer cells. Thereby, suppressing NRF2 in combination with paclitaxel can be a new and efficacious treatment approach in treating pancreatic cancer.

Keywords:  Combination therapy; Miapaca-2; NRF2; Paclitaxel; Pancreatic cancer; siRNA

DOI:  https://doi.org/10.1007/s12033-023-00872-2
Biology (Basel). 2023 Sep 04. pii: 1208. [Epub ahead of print]12(9):

Inhibition of LNC EBLN3P Enhances Radiation-Induced Mitochondrial Damage in Lung Cancer Cells by Targeting the Keap1/Nrf2/HO-1 Axis.

Haoyi Tang, Shanghai Liu, Xiangyu Yan, Yusheng Jin, Xiangyang He, Hao Huang, Lu Liu, Wentao Hu, Anqing Wu.

  Lung cancer remains the leading cause of cancer-related deaths in both women and men, claiming millions of lives worldwide. Radiotherapy is an effective modality for treating early-stage lung cancer; however, it cannot completely eradicate certain tumor cells due to their radioresistance. Radioresistance is commonly observed in conventionally fractionated radiotherapy, which can lead to treatment failure, metastasis, cancer recurrence, and poor prognosis for cancer patients. Identifying the underlying molecular mechanisms of radioresistance in lung cancer can promote the development of effective radiosensitizers, thereby improving patients' life expectancy and curability. In this study, we identified LNC EBLN3P as a regulator of lung cancer cell proliferation and radiosensitivity. The repression of LNC EBLN3P could increase ROS production and mitochondrial injury in NSCLC cells. In addition, knocking down LNC EBLN3P increased the binding of Nrf2 to Keap1, resulting in enhanced Nrf2 degradation, decreased translocation of Nrf2 to the nucleus, reduced expression of antioxidant protein HO-1, weakened cellular antioxidant capacity, and increased radiosensitivity of NSCLC cells. These findings suggest that targeting LNC EBLN3P could be a promising strategy for developing novel radiosensitizers in the context of conventional radiotherapy for NSCLC.

Keywords:  long non-coding RNA; lung cancer; mitochondrial damage; radiosensitivity; radiotherapy

DOI:  https://doi.org/10.3390/biology12091208
Biomed Pharmacother. 2023 Sep 22. pii: S0753-3322(23)01365-3. [Epub ahead of print]167 115567

Brusatol induces ferroptosis in oesophageal squamous cell carcinoma by repressing GSH synthesis and increasing the labile iron pool via inhibition of the NRF2 pathway.

Xu Zhu, Nannan Huang, Yao Ji, Xinling Sheng, Juanjuan Huo, Yuan Zhu, Menghuan Huang, Wei He, Junting Ma.

  Brusatol (Bru), a bioactive compound found in Brucea sumatrana, exerts antitumour effects on several malignancies. However, the role and molecular mechanism of Bru in squamous cell carcinoma of the oesophagus (ESCC) remain unclear. Here, we found that Bru decreased the survival of ESCC cells. Subsequently, the ferroptosis inhibitors, deferoxamine and liproxstatin-1, rescued Bru-induced cell death, indicating that ferroptosis plays a major role in Bru-induced cell death. Furthermore, Bru promoted lipid peroxidation, glutathione (GSH) depletion, and ferrous iron overload in vitro. Consistent with these in vitro results, Bru significantly inhibited tumour growth in KYSE150 xenograft nude mice by triggering ferroptosis. Mechanistically, nuclear factor E2-related factor 2 (NRF2) inactivation via increased ubiquitin-proteasome degradation was found to be a vital determinant of ferroptosis induced by Bru. Notably, Bru significantly decreases GSH synthesis, iron storage, and efflux by downregulating the expression of NRF2 target genes (glutamate-cysteine ligase catalytic subunit (GCLC), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), and solute carrier family 40 member 1 (SLC40A1)), resulting in the accumulation of lethal lipid-based reactive oxygen species (ROS) and intracellular enrichment of chelated iron. Taken together, our findings indicate that ferroptosis is a novel mechanism underlying Bru-induced antitumour activity and will hopefully provide a valuable compound for ESCC treatment.

Keywords:  Brusatol; Ferroptosis; Ferrous iron overload; GSH depletion; NRF2; Squamous cell carcinoma of the oesophagus

DOI:  https://doi.org/10.1016/j.biopha.2023.115567
BMC Pulm Med. 2023 Sep 25. 23(1): 360

Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer.

Chengmin Deng, Lin Xiong, Yang Chen, Kaifeng Wu, Jie Wu.

   BACKGROUND: Metformin is the most frequently prescribed medication for the treatment of type II diabetes mellitus and has played an anti-tumor potential in a variety of cancer types. Metformin can inhibit the growth of many cancer cells through various mechanisms, including ferroptosis. However, it is still unclear whether metformin can induce ferroptosis in lung cancer.
METHODS: This study evaluated the anti-tumor effect of metformin by detecting the levels of oxidative stress factors, the levels of ferrous ions, and the expression of ferroptosis-related genes in A549 and H1299 lung cancer cell lines treated with or without metformin.
RESULTS: The results showed that metformin treatment increased the levels of MDA, ROS and iron ions, while decreased the levels of GSH, T-SOD and CAT. Meanwhile, metformin treatment reduced the protein expression levels of Gpx4 and SLC7A11, Nrf2 and HO-1, while the addition of ferroptosis inhibitor ferrostatin-1 reversed the reduction.
CONCLUSIONS: These results demonstrated that metformin exerts anti-tumor effects by inducing ferroptosis through the Nrf2/HO-1 signaling pathway in lung cancer cells, providing a theoretical basis for drug therapy of lung cancer patients.

Keywords:  Ferroptosis; Lung cancer; Metformin; Nrf2/HO-1 signaling; Oxidative stress

DOI:  https://doi.org/10.1186/s12890-023-02655-6
Antioxidants (Basel). 2023 Sep 06. pii: 1728. [Epub ahead of print]12(9):

Redox Regulation of Nrf2 in Cisplatin-Induced Kidney Injury.

Kranti A Mapuskar, Casey F Pulliam, Diana Zepeda-Orozco, Benjamin R Griffin, Muhammad Furqan, Douglas R Spitz, Bryan G Allen.

  Cisplatin, a potent chemotherapeutic agent, is marred by severe nephrotoxicity that is governed by mechanisms involving oxidative stress, inflammation, and apoptosis pathways. The transcription factor Nrf2, pivotal in cellular defense against oxidative stress and inflammation, is the master regulator of the antioxidant response, upregulating antioxidants and cytoprotective genes under oxidative stress. This review discusses the mechanisms underlying chemotherapy-induced kidney injury, focusing on the role of Nrf2 in cancer therapy and its redox regulation in cisplatin-induced kidney injury. We also explore Nrf2's signaling pathways, post-translational modifications, and its involvement in autophagy, as well as examine redox-based strategies for modulating Nrf2 in cisplatin-induced kidney injury while considering the limitations and potential off-target effects of Nrf2 modulation. Understanding the redox regulation of Nrf2 in cisplatin-induced kidney injury holds significant promise for developing novel therapeutic interventions. This knowledge could provide valuable insights into potential strategies for mitigating the nephrotoxicity associated with cisplatin, ultimately enhancing the safety and efficacy of cancer treatment.

Keywords:  Nrf2; chemotherapy; kidney injury; metabolism; mitochondria; oxidative stress; reactive oxygen species; superoxide

DOI:  https://doi.org/10.3390/antiox12091728
Antioxidants (Basel). 2023 Sep 08. pii: 1739. [Epub ahead of print]12(9):

NRF2, a Superstar of Ferroptosis.

Ruihan Yan, Bingyi Lin, Wenwei Jin, Ling Tang, Shuming Hu, Rong Cai.

  Ferroptosis is an iron-dependent and lipid peroxidation-driven cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is key for cellular antioxidant responses, which promotes downstream genes transcription by binding to their antioxidant response elements (AREs). Numerous studies suggest that NRF2 assumes an extremely important role in the regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. Many pathological states are relevant to ferroptosis. Abnormal suppression of ferroptosis is found in many cases of cancer, promoting their progression and metastasis. While during tissue damages, ferroptosis is recurrently promoted, resulting in a large number of cell deaths and even dysfunctions of the corresponding organs. Therefore, targeting NRF2-related signaling pathways, to induce or inhibit ferroptosis, has become a great potential therapy for combating cancers, as well as preventing neurodegenerative and ischemic diseases. In this review, a brief overview of the research process of ferroptosis over the past decade will be presented. In particular, the mechanisms of ferroptosis and a focus on the regulation of ferroptosis by NRF2 will be discussed. Finally, the review will briefly list some clinical applications of targeting the NRF2 signaling pathway in the treatment of diseases.

Keywords:  NRF2; antioxidant; ferroptosis; metabolism

DOI:  https://doi.org/10.3390/antiox12091739
Turk J Gastroenterol. 2023 Sep 28.

Expression of Ferroptosis-Related Proteins Glutathione Peroxidase 4, Nuclear Factor Erythroid 2-Related Factor 2, and Solute Carrier Family 7 Member 11 in Gastric Cancer Patients.

Yitian Sun, Zhiyu Zhu, Ting Duan, Guoxiong Li.

BACKGROUND/AIMS: The aim of this study was to investigate the expression of ferroptosis-related targets glutathione peroxidase 4, nuclear factor erythroid 2-related factor 2, and solute carrier family 7 member 11 in gastric cancer and the correlation between their expression and the clinicopathological characteristics and prognosis of gastric cancer patients.
MATERIALS AND METHODS: Forty-two gastric cancer samples and paracancerous samples were included, and all cases were detected with glutathione peroxidase 4, nuclear factor erythroid 2-related factor 2, and solute carrier family 7 member 11 by immunohistochemistry. Six gastric cancer cell lines and 1 normal gastric epithelial cell were stably cultured, and the expression of target genes of different cell lines was detected using western blot and polymerase chain reaction. Public data were downloaded from the database, and analyses were performed by software including Statistical Package for the Social Sciences and Prism.
RESULTS: A high glutathione peroxidase 4 expression level was found in 7 (16.67%) cancer tissues and 0 (0.00%) paracancerous tissues (P = .012). Nuclear factor erythroid 2-related factor 2 was upregulated in 23 (54.76%) cancer tissues and 2 (4.76%) paracancerous tissues (P < .001). Solute carrier family 7 member 11 showed increased expression in 4 (9.52%) cancer tissues and 1 (2.38%) paracancerous tissue (P = .356). No significant association existed between their expression and the clinicopathological characteristics and prognosis of gastric cancer patients. Glutathione peroxidase 4 and nuclear factor erythroid 2-related factor 2 expressions were higher in all 6 gastric cancer cell lines compared to normal gastric epithelial cells.
CONCLUSION: Glutathione peroxidase 4 and nuclear factor erythroid 2-related factor 2 expressions were significantly higher in gastric cancer, which may be potential biomarkers of gastric cancer.

DOI: https://doi.org/10.5152/tjg.2023.22670
Int J Mol Sci. 2023 Sep 18. pii: 14215. [Epub ahead of print]24(18):

FGF2 Rescued Cisplatin-Injured Granulosa Cells through the NRF2-Autophagy Pathway.

Lihui Wang, Feiyan Cheng, Rumeng Pan, Zhiwei Cui, Jing She, Yidan Zhang, Xinyuan Yang.

  Premature ovarian failure (POF) is a complicated disorder related to the apoptosis of granulosa cells. The incidence of chemotherapy-associated POF is rising dramatically owing to the increasing proportion of cancer in adolescents. According to previous studies, oxidative stress caused by chemotherapeutic agents plays an important role in the development of POF. However, the exact effects of nuclear factor-erythroid 2-related factor2 (NRF2), a pivotal anti-oxidative factor, are still unknown in chemotherapy-associated POF. Firstly, we manipulated NRF2 expressions on a genetic or pharmaceutical level in cisplatin-injured granulosa cell models. The results indicate that the increasing NRF2 in cisplatin-injured cells was just compensatory and not enough to resist the accumulated stress. Upregulation of NRF2 could protect granulosa cells against cisplatin via elevating autophagic level by using an autophagic activator (rapamycin) and inhibitor (chloroquine). Additionally, exogenous FGF2 exerted a protective role by increasing NRF2 expression and promoting its nuclear translocation. Meanwhile, the results in cisplatin-POF mice models were consistent with what was found in injured cells. In conclusion, our research proved that FGF2 rescued cisplatin-injured granulosa cells through the NRF2-autophagy pathway and might provide a possible alternative treatment choice by targeting NRF2 for POF patients who are intolerant or unsuitable to FGF2.

Keywords:  FGF2; NRF2; POF; autophagy; chemotherapy

DOI:  https://doi.org/10.3390/ijms241814215