bims-nurfca 2024-02-11 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024–02–11
eight papers selected by
Caner Geyik, Istinye University

CTC together with Shh and Nrf2 are prospective diagnostic markers for HNSCC.
NRF2 activation in TRP53;P16 deficient mice drives oral squamous cell carcinoma.
Cephaeline promotes ferroptosis by targeting NRF2 to exert anti-lung cancer efficacy.
Fine particulate matter (PM2.5) induces the stem cell-like properties of hepatocellular carcinoma by activating ROS/Nrf2/Keap1-mediated autophagy.
FTO ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via P53-P21/Nrf2 activation in a HuR-dependent m6A manner.
A gain of function mutation in AKT1 increases hexokinase 2 and diminishes oxidative stress in meningioma.
Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.
Retraction Note: Ibrutinib facilitates the sensitivity of colorectal cancer cells to ferroptosis through BTK/NRF2 pathway.

BMC Mol Cell Biol. 2024 Feb 10. 25(1): 4

CTC together with Shh and Nrf2 are prospective diagnostic markers for HNSCC.

Md Mizanur Rahman, Muhammad Mosaraf Hossain, Shafiqul Islam, Ridwan Ahmed, Mohit Majumder, Shantu Dey, Md Kawser, Bishu Sarkar, Md Ejajur Rahman Himu, Ali Asgar Chowdhury, Shakera Ahmed, Supran Biswas, Mostafa Mahfuzul Anwar, Mohammad Jamal Hussain, Rajib Kumar Shil, Sunanda Baidya, Ramendu Parial, Mohammed Moinul Islam, Atul Bharde, Sreeja Jayant, Gourishankar Aland, Jayant Khandare, Shaikh Bokhtear Uddin, Abu Shadat Mohammod Noman.

   BACKGROUND: The lack of appropriate prognostic biomarkers remains a significant obstacle in the early detection of Head and Neck Squamous Cell Carcinoma (HNSCC), a cancer type with a high mortality rate. Despite considerable advancements in treatment, the success in diagnosing HNSCC at an early stage still needs to be improved. Nuclear factor erythroid 2-related factor 2 (Nrf2) and Sonic Hedgehog (Shh) are overexpressed in various cancers, including HNSCC, and have recently been proposed as possible therapeutic targets for HNSCC. Circulating Tumor Cell (CTC) is a novel concept used for the early detection of cancers, and studies have suggested that a higher CTC count is associated with the aggressiveness of HNSCC and poor survival rates. Therefore, we aimed to establish molecular markers for the early diagnosis of HNSCC considering Shh/Nrf2 overexpression in the background. In addition, the relation between Shh/Nrf2 and CTCs is still unexplored in HNSCC patients.
METHODS: In the present study, we selected a cohort of 151 HNSCC patients and categorized them as CTC positive or negative based on the presence or absence of CTCs in their peripheral blood. Data on demographic and clinicopathological features with the survival of the patients were analyzed to select the patient cohort to study Shh/Nrf2 expression. Shh and Nrf2 expression was measured by qRT-PCR.
RESULTS: Considering significant demographic [smoking, betel leaf (p-value < 0.0001)] and clinicopathological risk factors [RBC count (p < 0.05), Platelet count (p < 0.05), Neutrophil count (p < 0.005), MCV (p < 0.0001), NLR (p < 0.05), MLR (p < 0.05)], patients who tested positive for CTC also exhibited significant overexpression of Shh/Nrf2 in both blood and tissue compared to CTC-negative patients. A strong association exists between CTCs and tumor grade. Following chemotherapy (a combination of Cisplatin, 5FU, and Paclitaxel), the frequency of CTCs was significantly decreased in patients with HNSCC who had tested positive for CTCs. The Kaplan-Meier plot illustrated that a higher number of CTCs is associated with poorer overall survival (OS) in patients with HNSCC.
CONCLUSIONS: Detecting CTCs, and higher expression of Shh and Nrf2 in HNSCC patients' blood, can be a promising tool for diagnosing and prognosticating HNSCC.

Keywords:  CTC; Cancer; HNSCC; Nrf2; Shh

DOI:  https://doi.org/10.1186/s12860-024-00500-0
Cancer Res Commun. 2024 Feb 09.

NRF2 activation in TRP53;P16 deficient mice drives oral squamous cell carcinoma.

Samera H Hamad, Rani S Sellers, Nathan Wamsley, Paul Zolkind, Travis P Schrank, Michael B Major, Bernard E Weissman.

Aberrant activation of the NRF2/NFE2L2 transcription factor commonly occurs in head and neck squamous cell carcinomas (HNSCCs). Mouse model studies have shown that NRF2 activation alone does not result in cancer. When combined with classic oncogenes and at the right dose, NRF2 activation promotes tumor initiation and progression. Here we deleted the tumor suppressor genes p16INK4A and p53 (referred to as CP mice), which are commonly lost in human HNSCC, in the presence of a constitutively active NRF2E79Q mutant (CPN mice). NRF2E79Q expression in CPN mice resulted in squamous cell hyperplasia or dysplasia with hyperkeratosis in the esophagus, oropharynx, and forestomach. In addition, CPN mice displayed oral cavity squamous cell carcinoma (OSCC); CP mice bearing wild type NRF2 expression did not develop oral cavity hyperplasia, dysplasia or OSCC. In both CP and CPN mice, we also observed predominantly abdominal sarcomas and carcinomas. Our data show that in the context of p53 and p16 tumor suppressor loss, NRF2 activation serves oncogenic functions to drive OSCC. CPN mice represent a new model for OSCC that closely reflects the genetics of human HNSCC.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0386
Pharm Biol. 2024 Dec;62(1): 195-206

Cephaeline promotes ferroptosis by targeting NRF2 to exert anti-lung cancer efficacy.

Peng Chen, Qingxuan Ye, Shang Liang, Linghui Zeng.

   CONTEXT: Cephaeline is a natural product isolated from ipecac (Cephaelis ipecacuanha [Brot.] A. Rich. [Rubiaceae]). It exhibits promising anti-lung cancer activity and ferroptosis induction may be a key mechanism for its anti-lung cancer effect.
OBJECTIVES: This study investigates the anti-lung cancer activity and mechanisms of cephaeline both in vitro and in vivo.
MATERIALS AND METHODS: H460 and A549 lung cancer cells were used. The cephaeline inhibition rate on lung cancer cells was detected via a Cell Counting Kit-8 assay after treatment with cephaeline for 24 h. Subsequently, the concentrations of 25, 50 and 100 nM were used for in vitro experiments. In addition, the antitumour effects of cephaeline (5, 10 mg/kg) in vivo were evaluated after 12 d of cephaeline treatment.
RESULTS: Cephaeline showed significant inhibitory effects on lung cancer cells, and the IC50 of cephaeline on H460 and A549 at 24, 48 and 72 h were 88, 58 and 35 nM, respectively, for H460 cells and 89, 65 and 43 nM, respectively, for A549 cells. Meanwhile, we demonstrated that ferroptosis is the key mechanism of cephaeline against lung cancer. Finally, we found that cephaeline induced ferroptosis in lung cancer cells by targeting NRF2.
DISCUSSION AND CONCLUSION: We demonstrated for the first time that cephaeline inhibits NRF2, leading to ferroptosis in lung cancer cells. These findings may contribute to the development of innovative therapeutics for lung cancer.

Keywords:  GPX4; Natural products; SLC7A11; TBHQ; ipecac

DOI:  https://doi.org/10.1080/13880209.2024.2309891
Ecotoxicol Environ Saf. 2024 Feb 05. pii: S0147-6513(24)00127-1. [Epub ahead of print]272 116052

Fine particulate matter (PM2.5) induces the stem cell-like properties of hepatocellular carcinoma by activating ROS/Nrf2/Keap1-mediated autophagy.

Jiujiu Li, Haoqi Jiang, Yu Zhu, Zijian Ma, Bin Li, Jun Dong, Changchun Xiao, Anla Hu.

  Exposure to fine particulate matter (PM2.5) has been linked to an increased incidence and mortality of hepatocellular carcinoma (HCC). However, the impact of PM2.5 exposure on HCC progression and the underlying mechanisms remain largely unknown. This study aimed to investigate the effects of PM2.5 exposure on the stem cell-like properties of HCC cells. Our findings indicate that PM2.5 exposure significantly enhances the stemness of HCC cells (p < 0.01). Subsequently, male nude mice were divided into two groups (n = 8/group for tumor-bearing assay, n = 5/group for metastasis assay) for control and PM2.5 exposure. In vivo assays revealed that exposure to PM2.5 promoted the growth, metastasis, and epithelial-mesenchymal transition (EMT) of HCC cells (p < 0.01). Further exploration demonstrated that PM2.5 enhances the stemness of HCC cells by inducing cellular reactive oxygen species (ROS) generation (p < 0.05). Mechanistic investigation indicated that elevated intracellular ROS inhibited kelch-like ECH-associated protein 1 (Keap1) levels, promoting the upregulation and nucleus translocation of NFE2-like bZIP transcription factor 2 (Nrf2). This, in turn, induced autophagy activation, thereby promoting the stemness of HCC cells (p < 0.01). Our present study demonstrates the adverse effects of PM2.5 exposure on HCC development and highlights the mechanism of ROS/Nrf2/Keap1-mediated autophagy. For the first time, we reveal the impact of PM2.5 exposure on the poor prognosis-associated cellular phenotype of HCC and its underlying mechanism, which is expected to provide new theoretical basis for the improvement of public health.

Keywords:  Autophagy; Fine particulate matter; Hepatocellular carcinoma; Reactive oxygen species; Stemness

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116052
Redox Biol. 2024 Feb 02. pii: S2213-2317(24)00043-0. [Epub ahead of print]70 103067

FTO ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via P53-P21/Nrf2 activation in a HuR-dependent m6A manner.

Yunfan Yang, Jiajun Ren, Jifeng Zhang, Henghe Shi, Junnan Wang, Youyou Yan.

  Doxorubicin (DOX)-induced cardiotoxicity seriously limits its clinical applicability, and no therapeutic interventions are available. Ferroptosis, an iron-dependent regulated cell death characterised by lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. N6-methyladenosine (m6A) methylation is the most frequent type of RNA modification and involved in DOX-induced ferroptosis, however, its underlying mechanism remains unclear. P21 was recently found to inhibit ferroptosis by interacting with Nrf2 and is regulated in a P53-dependent or independent manner, such as through m6A modification. In the present study, we investigated the mechanism underlying m6A modification in DOX-induced ferroptosis by focusing on P21. Our results show that fat mass and obesity-associated protein (FTO) down-regulation was associated with DOX-induced cardiotoxicity. FTO over-expression significantly improved cardiac function and cell viability in DOX-treated mouse hearts and H9C2 cells. FTO over-expression significantly inhibited DOX-induced ferroptosis, and the Fer-1 inhibition of ferroptosis significantly reduced DOX-induced cardiotoxicity. P21 was significantly upregulated by FTO and activated Nrf2, playing a crucial role in the anti-ferroptotic effect. FTO upregulated P21/Nrf2 in a P53-dependent manner by mediating the demethylation of P53 or in a P53-independent manner by mediating P21/Nrf2 directly. Human antigen R (HuR) is crucial for FTO-mediated regulation of ferroptosis and P53-P21/Nrf2. Notably, we also found that P21 inhibition in turn inhibited HuR and P53 expression, while HuR inhibition further inhibited FTO expression. RNA immunoprecipitation assay showed that HuR binds to the transcripts of FTO and itself. Collectively, FTO inhibited DOX-induced ferroptosis via P21/Nrf2 activation by mediating the m6A demethylation of P53 or P21/Nrf2 in a HuR-dependent manner and constituted a positive feedback loop with HuR and P53-P21. Our findings provide novel insight into key functional mechanisms associated with DOX-induced cardiotoxicity and elucidate a possible therapeutic approach.

Keywords:  Doxorubicin; FTO; Ferroptosis; HuR; P21; P53; m6A modification

DOI:  https://doi.org/10.1016/j.redox.2024.103067
Cytokine. 2024 Feb 06. pii: S1043-4666(24)00038-3. [Epub ahead of print]176 156535

A gain of function mutation in AKT1 increases hexokinase 2 and diminishes oxidative stress in meningioma.

Swati Singh, Kirti Lathoria, Sonia B Umdor, Jyotsna Singh, Vaishali Suri, Ellora Sen.

  Increasing evidence suggests the oncogenic role of missense mutation (AKT1-E17K) of AKT1 gene in meningiomas. Upon investigating the connection between the pro-tumorigenic role of AKT1-E17K and cellular metabolic adaptations, elevated levels of glycolytic enzyme hexokinase 2 (HK2) was observed in meningioma patients with AKT1-E17K compared to patients harboring wild-type AKT1. In vitro experiments also suggested higher HK2 levels and its activity in AKT1-E17K cells. Treatment with the conventional drug of choice AZD5363 (a pan AKT inhibitor) enhanced cell death and diminished HK2 levels in AKT1 mutants. Given the role of AKT phosphorylation in eliciting inflammatory responses, we observed increased levels of inflammatory mediators (IL-1β, IL6, IL8, and TLR4) in AKT1-E17K cells compared to AKT1-WT cells. Treatment with AKT or HK2 inhibitors dampened the heightened levels of inflammatory markers in AKT1-E17K cells. As AKT and HK2 regulates redox homeostasis, diminished ROS generation concomitant with increased levels of NF-E2- related factor 2 (Nrf2) and superoxide dismutase 1 (SOD1) were observed in AKT1-E17K cells. Increased sensitivity of AKT1-E17K cells to AZD5363 in the presence of HK2 inhibitor Lonidamine was reversed upon treatment with ROS inhibitor NAC. By affecting metabolism, inflammation, and redox homeostasis AKT1-E17K confers a survival advantage in meningioma cells. Our findings suggest that targeting AKT-HK2 cross-talk to induce ROS-dependent cell death could be exploited as novel therapeutic approach in meningiomas.

Keywords:  AKT1-E17K; Hexokinase; Inflammation; Meningioma; Nrf2; Oxidative stress

DOI:  https://doi.org/10.1016/j.cyto.2024.156535
Int J Mol Sci. 2024 Feb 03. pii: 1857. [Epub ahead of print]25(3):

Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.

Fu-Chen Kuo, Hsin-Yi Tsai, Bi-Ling Cheng, Kuen-Jang Tsai, Ping-Chen Chen, Yaw-Bin Huang, Chung-Jung Liu, Deng-Chyang Wu, Meng-Chieh Wu, Bin Huang, Ming-Wei Lin.

  Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor's phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Keywords:  M2-type macrophage; Nrf2; endothelial cells; melanoma; mitochondrial transplantation; tumor growth; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25031857
Cell Death Dis. 2024 Feb 07. 15(2): 116

Retraction Note: Ibrutinib facilitates the sensitivity of colorectal cancer cells to ferroptosis through BTK/NRF2 pathway.

Jin-Feng Zhu, Yi Liu, Wen-Ting Li, Ming-Hui Li, Chao-Hui Zhen, Pei-Wei Sun, Ji-Xin Chen, Wen-Hao Wu, Wei Zeng.

DOI: https://doi.org/10.1038/s41419-024-06498-9