bims-nurfca 2023-12-10 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–12–10
ten papers selected by
Caner Geyik, Istinye University

Lymphoid-specific helicase inhibits cervical cancer cells ferroptosis by promoting Nrf2 expression.
RASSF1A promotes radiosensitivity in nasopharyngeal carcinoma by promoting FoxO3a and inhibiting the Nrf2/TXNRD1 signaling pathway.
NR0B1 suppresses ferroptosis through upregulation of NRF2/c-JUN-CBS signaling pathway in lung cancer cells.
Yi-qi-hua-yu-jie-du decoction induces ferroptosis in cisplatin-resistant gastric cancer via the AKT/GSK3β/NRF2/GPX4 axis.
Induced oxidative stress and apoptosis by 1-bromopropane in SH-SY5Y cells correlates with inhibition of Nrf2 function.
Tumor-immune microenvironment and NRF2 associate with clinical efficacy of PD-1 blockade combined with chemotherapy in lung squamous cell carcinoma.
Plasma-activated medium ameliorates the chemoresistance of human lung adenocarcinoma cells mediated via downregulation of claudin-2 expression.
Role of Farnesoid Receptors and Nrf2-mediated Genes in Gentamicin-induced Nephrotoxicity in Rat: A Time-course Study.
Taxifolin protects against doxorubicin-induced cardiotoxicity and ferroptosis by adjusting microRNA-200a-mediated Nrf2 signaling pathway.
CXCL10 and Nrf2-upregulated mesenchymal stem cells reinvigorate T lymphocytes for combating glioblastoma.

PeerJ. 2023 ;11 e16451

Lymphoid-specific helicase inhibits cervical cancer cells ferroptosis by promoting Nrf2 expression.

Weiwei Tie, Fenfen Ge.

   Background: Cervical cancer is a major cause of morbidity and mortality in women worldwide. The underlying mechanisms of its progression are not well understood. In this study, we investigated the role of lymphoid-specific helicase (HELLS) in cervical cancer.
Methods: We measured HELLS expression in cervical cancer and assessed its function using gain- and loss-of-function experiments. Cell viability was measured using the Cell Counting Kit-8 (CCK8 ) assay, and cell proliferation was analyzed using colony formation and EdU assays.
Results: We found that HELLS was significantly increased in cervical cancer and that its overexpression promoted cell viability (P < 0.01) and colony formation (P < 0.001). In contrast, si-HELLS suppressed these effects. Moreover, HELLS overexpression inhibited cell death induced by the ferroptosis inducer erastin (P < 0.01). Mechanistically, we found that HELLS promoted cervical cancer proliferation by regulating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated ferroptosis.
Conclusion: Our data suggest that HELLS promotes cervical cancer proliferation by inhibiting Nrf2 expression. Therefore, HELLS knockdown may be an effective treatment for cervical cancer.

Keywords:  Cervical cancer; Ferroptosis; Lymphoid-specific helicase; Nuclear factor erythroid 2-related factor 2

DOI:  https://doi.org/10.7717/peerj.16451
Neoplasma. 2023 Oct;pii: 221122N1124. [Epub ahead of print]70(5): 633-644

RASSF1A promotes radiosensitivity in nasopharyngeal carcinoma by promoting FoxO3a and inhibiting the Nrf2/TXNRD1 signaling pathway.

Yishimei Si, Linghan Meng, Bingwen Zhang, Yuanqing Wu, Qianming Du, Jinjing Xu, Jianwei Qi.

Radiotherapy is widely used as the first-line treatment for nasopharyngeal carcinoma (NPC). However, the resistance of some patients to treatment lowers its clinical effectiveness. Compared to typical epithelial cells, NPC markedly lowers the Ras-association domain family 1A (RASSF1A) protein expression. RASSF1A overexpression sensitizes NPC cells to radiotherapy. Mechanistically, RASSF1A promotes the expression of Forkhead box O3a (FoxO3a) in the nucleus and inhibits the Nuclear factor E2-related factor 2 (Nrf2) signaling pathway via binding to the Kelch-like ECH-associated protein 1 (Keap1) promoter. Through elevating intracellular ROS levels, RASSF1A overexpression inhibits the expression of thioredoxin reductase 1 (TXNRD1), a crucial Nrf2 target gene, and increases NPC sensitivity to radiation. Immunohistochemical staining of NPC tissue sections revealed that the expression of RASSF1A is negatively correlated with that of TXNRD1. The traditional Chinese medicine component andrographolide (AGP), which induces RASSF1A expression, increased the sensitivity of NPC cells to radiotherapy in vitro and in vivo. Our findings implied that RASSF1A increases the sensitivity of NPC to radiation by increasing FoxO3a expression in the nucleus, inhibiting the Nrf2/TXNRD1 signaling pathway, and elevating intracellular ROS levels. AGP targets RASSF1A and may be a promising adjuvant sensitizer for enhancing radiosensitivity in NPC.

DOI: https://doi.org/10.4149/neo_2023_221122N1124
Am J Cancer Res. 2023 ;13(11): 5174-5196

NR0B1 suppresses ferroptosis through upregulation of NRF2/c-JUN-CBS signaling pathway in lung cancer cells.

Xin-Yue Zhang, Hao Zhang, Si-Jing Hu, Shun-Yao Liao, Da-Chang Tao, Xiao-Lan Tan, Ming Yi, Xiang-You Leng, Zhao-Kun Wang, Jia-Ying Shi, Sheng-Yu Xie, Yuan Yang, Yun-Qiang Liu.

Ferroptosis has demonstrated significant potential in treating radiochemotherapy-resistant cancers, but its efficacy can be affected by recently discovered ferroptosis suppressors. In this study, we discovered that NR0B1 protects against erastin- or RSL3-induced ferroptosis in lung cancer cells. Transcriptomic analysis revealed that NR0B1 significantly interfered with the expression of 12 ferroptosis-related genes, and the expression level of NR0B1 positively correlated with that of c-JUN, NRF2, and CBS. We further revealed that NR0B1 suppression of ferroptosis depended on the activities of c-JUN, NRF2, and CBS. NR0B1 directly promoted the expression of NRF2 and c-JUN and indirectly upregulated CBS expression through enhancing NRF2 and/or c-JUN transcription. Moreover, we showed that NR0B1 depletion restrained xenograft tumor growth and facilitated RSL3-induced ferroptosis in the tumors. In conclusion, our findings uncover that NR0B1 suppresses ferroptosis by activating the c-JUN/NRF2-CBS signaling pathway in lung cancer cells, providing new evidence for the involvement of NR0B1 in drug resistance during cancer therapy.

Keywords: CBS; NR0B1; NRF2; c-JUN; drug resistance; ferroptosis; lung cancer
Phytomedicine. 2023 Nov 18. pii: S0944-7113(23)00579-2. [Epub ahead of print]123 155220

Yi-qi-hua-yu-jie-du decoction induces ferroptosis in cisplatin-resistant gastric cancer via the AKT/GSK3β/NRF2/GPX4 axis.

Wenjie Huang, Fang Wen, Peipei Yang, Ye Li, Qiurong Li, Peng Shu.

   BACKGROUND: Resistance to chemotherapy in gastric cancer (GC) is a ubiquitous challenge for its treatment. Yi-qi-hua-yu-jie-du decoction (YJD), an empirical formula in Traditional Chinese Medicine (TCM), demonstrated survival-prolonging functions in patients with GC. Previous research has shown that YJD could also inhibit drug resistance in GC. However, the precise mechanisms for how YJD accomplishes this remain incompletely explained.
PURPOSE: The research aimed to identify differential metabolic characteristics in cisplatin-resistant GC and investigate whether YJD can target these differences to suppress GC drug resistance.
METHODS: Metabolomic analysis was conducted to identify metabolic disparities between cisplatin-resistant and parental GC cells, as well as metabolic modifications resulting from YJD intervention in cisplatin-resistant GC cells. The effect of YJD on ferroptosis stimulation was assessed by measuring the levels of reactive oxygen species (ROS), malondialdehyde (MDA), iron ions, the reduced glutathione (GSH) to oxidised glutathione (GSSG) ratio, and alterations in mitochondrial morphology. Western blotting and quantitative real-time polymerase chain reaction (Q-PCR) were employed to verity the mechanisms of YJD-triggered ferroptosis through GPX4 and NRF2 overexpression models, alongside the AKT activator SC79. In vivo validation was conducted using nude mouse xenograft models.
RESULTS: Cisplatin-resistant GC exhibited altered GSH/GPX4 metabolism, and ferroptosis was a significantly enriched cell death pattern with YJD treatment in cisplatin-resistant GC cells. Ferroptosis biomarkers, including ROS, MDA, iron ions, the GSH/GSSG ratio, and mitochondrial morphology, were remarkably changed with the YJD intervention. Mechanistic experiments demonstrated that YJD inhibited the phosphorylation cascade activity of the AKT/GSK3β pathway, thereby reducing NRF2 expression. The level of GPX4, a crucial enzyme involved in glutathione metabolism, was attenuated, facilitating ferroptosis induction in cisplatin-resistant GC.
CONCLUSION: The research reveals, for the first time, changes in GSH/GPX4 metabolism in cisplatin-resistant GC cells based on metabolomic analysis. YJD induced ferroptosis in cisplatin-resistant GC by inhibiting GPX4 through the AKT/GSK3β/NRF2 pathway, thus attenuating the cisplatin drug resistance in GC. Our findings identify metabolic changes in cisplatin-resistant GC and establish a theoretical framework for YJD on tackling drug resistance in GC through ferroptosis.

Keywords:  Drug resistance; Ferroptosis; GPX4; Gastric cancer; Traditional Chinese medicine

DOI:  https://doi.org/10.1016/j.phymed.2023.155220
Drug Chem Toxicol. 2023 Dec 04. 1-11

Induced oxidative stress and apoptosis by 1-bromopropane in SH-SY5Y cells correlates with inhibition of Nrf2 function.

Guangtao Yang, Wei Zhou, Minhong Zhang, Xiaohuan Zhong, Haili Qiu, Yingping Xiang, Zhimin Zhang, Peimao Li, Dianpeng Wang.

  In this study, we established SH-SY5Y human neuroblastoma cells as an in vitro model to investigate whether oxidative stress and the nuclear erythroid-2 related factor 2 (Nrf2) signaling pathway are associated with 1-bromopropane (1-BP) -induced nerve cell injury. We identified that 1-BP exhibited neurotoxicity mainly through oxidant-based processes in SH-SY5Y cells, as reactive oxygen species, malondialdehyde levels, and 8-hydroxy-2' -deoxyguanosine significantly increased, while superoxide dismutase activity decreased. Furthermore, Nrf2 translocation from the cytosol to the nucleus was inhibited, as was downstream protein expression of the Nrf2-regulated genes HO-1 and Bcl-2. Activation of caspase-9 and -3 increased, and apoptosis was observed. Vitamin C alleviated 1-BP-induced apoptosis by decreasing oxidative stress and activating the Nrf2 signaling pathway. Knockdown of Nrf2 in SH-SY5Y cells increased 1-BP-induced reactive oxygen species production and cell apoptosis, and inhibited HO-1 and Bcl-2 protein expression, while overexpression of Nrf2 alleviated these processes. These findings suggest that 1-BP-induced oxidative stress and apoptosis in SH-SY5Y cells are associated with Nrf2 function inhibition.

Keywords:  1-bromopropane; CRISP R/Cas9; Nrf2; SH-SY5Y; oxidative stress

DOI:  https://doi.org/10.1080/01480545.2023.2288795
Cell Rep Med. 2023 Nov 28. pii: S2666-3791(23)00496-2. [Epub ahead of print] 101302

Tumor-immune microenvironment and NRF2 associate with clinical efficacy of PD-1 blockade combined with chemotherapy in lung squamous cell carcinoma.

Jianchun Duan, Yun Zhang, Ran Chen, Liang Liang, Yi Huo, Shun Lu, Jun Zhao, Chunhong Hu, Yuping Sun, Kunyu Yang, Mingwei Chen, Yan Yu, Jianming Ying, Ruiqi Huang, Xiaopeng Ma, Shiangjiin Leaw, Fan Bai, Zhirong Shen, Shangli Cai, Daming Gao, Jie Wang, Zhijie Wang.

  The RATIONALE-307 study (ClinicalTrials.gov: NCT03594747) demonstrates prolonged progression-free survival (PFS) with first-line tislelizumab plus chemotherapy versus chemotherapy in advanced lung squamous cell carcinoma (LUSC; N = 360). Here we describe an immune-related gene expression signature (GES), composed of genes involved in both innate and adaptive immunity, that appears to differentiate tislelizumab plus chemotherapy PFS benefit versus chemotherapy. In contrast, a tislelizumab plus chemotherapy PFS benefit is observed regardless of programmed death ligand 1 (PD-L1) expression or tumor mutational burden (TMB). Genetic analysis reveals that NRF2 pathway activation is enriched in PD-L1positive and TMBhigh patients. NRF2 pathway activation is negatively associated with PFS, which affects efficacy outcomes associated with PD-L1 and TMB status, impairing their predictive potential. Mechanistic studies demonstrate that NRF2 directly mediates PD-L1 constitutive expression independent of adaptive PD-L1 regulation in LUSC. In summary, the GES is an immune signature that might identify LUSC patients likely to benefit from first-line tislelizumab plus chemotherapy.

Keywords:  NRF2; PD-1 blockade; PD-L1; biomarkers; clinical trial; gene expression signature; immunotheraphy; squamous NSCLC; tislelizumab; tumor mutational burden

DOI:  https://doi.org/10.1016/j.xcrm.2023.101302
Arch Biochem Biophys. 2023 Dec 04. pii: S0003-9861(23)00345-4. [Epub ahead of print] 109846

Plasma-activated medium ameliorates the chemoresistance of human lung adenocarcinoma cells mediated via downregulation of claudin-2 expression.

Hiroaki Eguchi, Yaqing Yu, Yuta Yoshino, Hirokazu Hara, Hiromasa Tanaka, Akira Ikari.

  Plasma-activated medium (PAM) has various biological activities including anticancer and antimicrobial. However, the effect on chemoresistance in cancer cells has not been clarified in detail. Solid cancer cells form a microenvironment in the body and acquire resistance against anticancer drugs. So far, we reported that claudin-2 (CLDN2), a component of tight junctions, suppresses the anticancer drug-induced cytotoxicity of spheroids that mimic in vivo tumors. Here, we found that the protein level of CLDN2 is downregulated by the sublethal concentration of PAM in human lung adenocarcinoma-derived A549 and PC-3 cells. A cycloheximide pulse-chase assay showed that PAM accelerates the degradation of CLDN2 protein. The PAM-induced reduction of CLDN2 protein was inhibited by a lysosome inhibitor, indicating PAM may enhance the lysosomal degradation of CLDN2. The paracellular permeability to doxorubicin (DXR), an anthracycline antitumor drug, was enhanced by PAM. In the spheroids, the accumulation and toxicity of DXR were enhanced by PAM. In addition, oxidative stress and the expression of nuclear factor erythroid 2-related factor 2, one of the key factors for the acquisition of chemoresistance, were attenuated by PAM. The improvement effect of PAM on chemoresistance was suppressed by the exogenous CLDN2 overexpression. These results indicate that PAM has the ability to downregulate CLDN2 expression and may become an adjuvant drug against lung adenocarcinoma.

Keywords:  Chemoresistance; Claudin-2; Lung cancer; Plasma

DOI:  https://doi.org/10.1016/j.abb.2023.109846
Iran J Kidney Dis. 2023 Nov;17(6): 294-305

Role of Farnesoid Receptors and Nrf2-mediated Genes in Gentamicin-induced Nephrotoxicity in Rat: A Time-course Study.

Mohammad Reza Ashrafi, Azadeh Khalili, Seyed Ali Hashemi, Roham Mazloom, Saeed Changizi-Ashtiyani, Gholamreza Bayat.

INTRODUCTION: Farnesoid-X-activated receptor (FXR) is considered as an upstream controller which could influence the other key regulatory genes encoding cellular antioxidant defense system.
METHODS: Thirty-five male Wistar rats (240 ± 20 g) were randomly allocated into five groups: 1) control, 2) received gentamicin (100 mg/kg/d) for three days (GM-3d), 3) seven days (GM-7d), 4) 10 days (GM-10d), and 5) 14 consecutive days (GM-14d). Biochemical measurements of BUN and serum creatinine (SCr), histological assessment of renal samples as well as molecular analysis using real-time qRT-PCR were used to investigate the pattern of changes in different levels.
RESULTS: Administration of gentamicin was associated with a significant increase in the BUN and SCr until the 10th day, which then suddenly dropped at the day 14. Meantime, the maximum histological distortion was also seen on the 10th day but in a similar pattern, 14th day was associated with clear improvement. Compared to the control value, the maximum reduction in the mRNA expression of Farnesoid X-activated receptor (FXR), nuclear factor erythroid 2-related factor 2 (Nrf2) and Glutathione cysteine ligase-modulatory subunit (GCLM), occurred at the 3rd and 7th days, respectively. Compared to the control, the mRNA expression of the mentioned genes significantly increased up to day 14. Apart from the 3rd day, the mRNA expression of alpha-glutathione S-transferase (α-GST) and superoxide dismutase (SOD) showed a similar descending and ascending pattern at 7th and 10th days, respectively.
CONCLUSION: The expression of FXR, as an upstream controller gene and its downstream pathways mediated by Nrf2, could play a role in gentamicin-induced nephrotoxicity but the pattern of expression was rather biphasic at the acute phase or the subacute ones. DOI: 10.52547/ijkd.7523.
Heliyon. 2023 Nov;9(11): e22011

Taxifolin protects against doxorubicin-induced cardiotoxicity and ferroptosis by adjusting microRNA-200a-mediated Nrf2 signaling pathway.

Zhihui Lin, Jie Wang.

  The chemotherapeutic agent doxorubicin (Dox) is commonly used to treat various types of cancer, even though it can cause life-threatening cardiotoxicity. Clinically, there is no particularly effective way to treat Dox-induced cardiotoxicity. Therefore, it is imperative to identify compounds that can effectively alleviate Dox-induced cardiotoxicity. Ferroptosis and oxidative stress play a key role in Dox-induced cardiotoxicity, and the inhibition of ferroptosis and oxidative stress could effectively protect against doxorubicin-induced cardiotoxicity. Taxifolin (TAX) is a flavonoid commonly found in onions and citrus fruits. In the present study, we evaluated the effects of TAX on Dox-induced cardiac injury and dysfunction and aimed to explore the mechanisms underlying these effects. Using a mouse model of Dox-induced cardiotoxicity, we administered 20 mg/kg/day of TAX by gavage for 2 weeks. A week after the first use of TAX, each mouse was administered a 10 mg/kg dose of Dox. TAX was first evaluated for its cardioprotective properties, and the outcomes showed that TAX significantly reduced the damage caused by Dox to the myocardium in terms of structural and functional damage by effectively inhibiting ferroptosis and oxidative stress. In vivo, echocardiography, histopathologic assay, serum biochemical analysis and western blotting was used to find the results that Dox promoted ferroptosis-induced cardiomyocyte death, while TAX reversed these effects. In vitro, we also found that TAX alleviated Dox-induced cardiotoxicity by using ROS/DHE staining assay, Cellular immunofluorescence and western blotting. TAX increasing expression of microRNA-200a (miR-200a) which affects ferroptosis by activating Nrf2 signaling pathway. We believe that TAX inhibits ferroptosis and is a potential phytochemical that prevents Dox-induced cardiotoxicity.

Keywords:  Cardiotoxicity; Doxorubicin; Ferroptosis; Nrf2; Taxifolin; miR-200a

DOI:  https://doi.org/10.1016/j.heliyon.2023.e22011
J Immunother Cancer. 2023 Dec 06. pii: e007481. [Epub ahead of print]11(12):

CXCL10 and Nrf2-upregulated mesenchymal stem cells reinvigorate T lymphocytes for combating glioblastoma.

Jiaji Mao, Jianing Li, Junwei Chen, Qin Wen, Minghui Cao, Fang Zhang, Baoxun Li, Qinyuan Zhang, Zhe Wang, Jingzhong Zhang, Jun Shen.

   BACKGROUND: Lack of tumor-infiltrating T lymphocytes and concurrent T-cell dysfunction have been identified as major contributors to glioblastoma (GBM) immunotherapy resistance. Upregulating CXCL10 in the tumor microenvironment (TME) is a promising immunotherapeutic approach that potentially increases tumor-infiltrating T cells and boosts T-cell activity but is lacking effective delivery methods.
METHODS: In this study, mesenchymal stem cells (MSCs) were transduced with a recombinant lentivirus encoding Cxcl10, Nrf2 (an anti-apoptosis gene), and a ferritin heavy chain (Fth) reporter gene in order to increase their CXCL10 secretion, TME survival, and MRI visibility. Using FTH-MRI guidance, these cells were injected into the tumor periphery of orthotopic GL261 and CT2A GBMs in mice. Combination therapy consisting of CXCL10-Nrf2-FTH-MSC transplantation together with immune checkpoint blockade (ICB) was also performed for CT2A GBMs. Thereafter, in vivo and serial MRI, survival analysis, and histology examinations were conducted to assess the treatments' efficacy and mechanism.
RESULTS: CXCL10-Nrf2-FTH-MSCs exhibit enhanced T lymphocyte recruitment, oxidative stress tolerance, and iron accumulation. Under in vivo FTH-MRI guidance and monitoring, peritumoral transplantation of CXCL10-Nrf2-FTH-MSCs remarkably inhibited orthotopic GL261 and CT2A tumor growth in C57BL6 mice and prolonged animal survival. While ICB alone demonstrated no therapeutic impact, CXCL10-Nrf2-FTH-MSC transplantation combined with ICB demonstrated an enhanced anticancer effect for CT2A GBMs compared with transplanting it alone. Histology revealed that peritumorally injected CXCL10-Nrf2-FTH-MSCs survived longer in the TME, increased CXCL10 production, and ultimately remodeled the TME by increasing CD8+ T cells, interferon-γ+ cytotoxic T lymphocytes (CTLs), GzmB+ CTLs, and Th1 cells while reducing regulatory T cells (Tregs), exhausted CD8+ and exhausted CD4+ T cells.
CONCLUSIONS: MRI-guided peritumoral administration of CXCL10 and Nrf2-overexpressed MSCs can significantly limit GBM growth by revitalizing T lymphocytes within TME. The combination application of CXCL10-Nrf2-FTH-MSC transplantation and ICB therapy presents a potentially effective approach to treating GBM.

Keywords:  brain neoplasms; cell engineering; immunotherapy; lymphocytes, tumor-infiltrating; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-007481