bims-nurfca 2024-03-31 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024–03–31
ten papers selected by
Caner Geyik, Istinye University

KEAP1-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype.
Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
Juglone induces ferroptosis in glioblastoma cells by inhibiting the Nrf2-GPX4 axis through the phosphorylation of p38MAPK.
Involvement of ferroptosis in eribulin-induced cytotoxicity in ovarian clear cell carcinoma.
Camptothecin enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.
AURKA emerges as a vulnerable target for KEAP1-deficient non-small cell lung cancer by activation of asparagine synthesis.
Cell-Cycle-related Protein Centromere Protein F Deficiency Inhibits Cervical Cancer Cell Growth by Inducing Ferroptosis Via Nrf2 Inactivation.
Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11.
IL-1α facilitates GSH synthesis to counteract oxidative stress in oral squamous cell carcinoma under glucose-deprivation.
Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway.

Int J Mol Sci. 2024 Mar 20. pii: 3510. [Epub ahead of print]25(6):

KEAP1-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype.

Christopher J Occhiuto, Karen T Liby.

  Considerable advances have been made in lung cancer therapies, but there is still an unmet clinical need to improve survival for lung cancer patients. Immunotherapies have improved survival, although only 20-30% of patients respond to these treatments. Interestingly, cancers with mutations in Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, are resistant to immune checkpoint inhibition and correlate with decreased lymphoid cell infiltration. NRF2 is known for promoting an anti-inflammatory phenotype when activated in immune cells, but the study of NRF2 activation in cancer cells has not been adequately assessed. The objective of this study was to determine how lung cancer cells with constitutive NRF2 activity interact with the immune microenvironment to promote cancer progression. To assess, we generated CRISPR-edited mouse lung cancer cell lines by knocking out the KEAP1 or NFE2L2 genes and utilized a publicly available single-cell dataset through the Gene Expression Omnibus to investigate tumor/immune cell interactions. We show here that KEAP1-mutant cancers promote immunosuppression of the tumor microenvironment. Our data suggest KEAP1 deletion is sufficient to alter the secretion of cytokines, increase expression of immune checkpoint markers on cancer cells, and alter recruitment and differential polarization of immunosuppressive macrophages that ultimately lead to T-cell suppression.

Keywords:  KEAP1; M2 polarization; NRF2 pathway; immunosuppression; lung cancer; macrophages

DOI:  https://doi.org/10.3390/ijms25063510
Sci Adv. 2024 Mar 29. 10(13): eadm9859

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Ray Pillai, Sarah E LeBoeuf, Yuan Hao, Connie New, Jenna L E Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I Sayin, Kamal M Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T Poirier, Charles M Rudin, Shawn M Davidson, Sergei B Koralov, Thales Papagiannakopoulos.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

DOI: https://doi.org/10.1126/sciadv.adm9859
Chin Med. 2024 Mar 22. 19(1): 52

Juglone induces ferroptosis in glioblastoma cells by inhibiting the Nrf2-GPX4 axis through the phosphorylation of p38MAPK.

Fangzhou Guo, Guoyuan Ling, Jianting Qiu, Jicheng Li, Yu Gan, YingYing Yu, Jiamei Tang, Ligen Mo, Haozhe Piao.

   BACKGROUND: Ferroptosis, a non-apoptotic form of cell death induced by accumulation of free iron ions and lipid peroxidation, its importance for cancer treatment is gradually being recognized. Research on the anti-cancer mechanism of juglone is accumulating. However, the specific mechanism by which it directs glioblastoma (GBM) to death is unknown.
METHODS: We used in vitro and in vivo experiments to explore the anti-GBM effect generated by juglone through the ferroptosis pathway.
RESULTS: Juglone mainly causes cell death by inducing ferroptosis. Mechanistically, juglone can significantly activate the phosphorylation of p38MAPK. According to transcriptome sequencing and protein interaction analysis, the Nrf2-GPX4 signaling pathway is identified as the primary pathway through which juglone mediates ferroptosis. In vitro and in vivo experiments further verified that juglone induces the ferroptosis of GBM by activating the phosphorylation of p38MAPK and negatively regulating the Nrf2-GPX4 signaling pathway.
CONCLUSION: Juglone induces ferroptosis and inhibits the growth of GBM by targeting the Nrf2/Gpx4 signaling pathway and thus holds promise as a novel ferroptosis inducer or anti-GBM drug.

Keywords:  Ferroptosis; Glioblastoma; Juglone; Nrf2; p38MAPK

DOI:  https://doi.org/10.1186/s13020-024-00920-2
Eur J Pharmacol. 2024 Mar 27. pii: S0014-2999(24)00232-2. [Epub ahead of print] 176544

Involvement of ferroptosis in eribulin-induced cytotoxicity in ovarian clear cell carcinoma.

Mana Azumi, Kazuya Kusama, Mikihiro Yoshie, Saya Nakano, Atsuya Tsuru, Tomoyasu Kato, Kazuhiro Tamura.

  Ovarian clear cell carcinoma (OCCC) is a unique clinicopathological subtype of epithelial ovarian cancer that is resistant to standard chemotherapy. Eribulin, a microtubule dynamics inhibitor of halichondrin class, has unique effects in the cancer microenvironment such as induction of epithelization and reduction in metastatic potential in breast cancer cells; however, nothing is known about the effect of eribulin and the detailed mechanisms in OCCC. This study aimed to investigate the involvement of ferroptosis and its mechanism in the antitumor activity of eribulin in OCCC cells and a mouse xenograft model. We found that eribulin-induced cell death was reduced by ferroptosis inhibitors; deferoxamine, an iron chelator and ferrostatin-1, a lipid peroxidation inhibitor. Eribulin increased the levels of intracellular iron, reactive oxygen species (ROS), and lipid peroxides, and increased the mitochondrial membrane potential. Eribulin downregulated the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), and superoxide dismutase (SOD) activity. The combination of eribulin and ML210, a glutathione peroxidase 4-inhibiting ferroptosis inducer, had a synergistic effect on ferroptosis. Taken together, our findings show firstly that eribulin triggers ferroptosis in OCCC and this effect occurs via the suppression of the Nrf2-HO-1 signaling pathway, SOD activity and the promotion of lipid peroxidation. These findings suggest that eribulin-induced ferroptosis is associated with its anti-tumor effect and also could be a potential therapeutic target in OCCC.

Keywords:  Dihydroorotate dehydrogenase; Eribulin; Ferroptosis; Mitochondria; Nrf2; Ovarian clear cell carcinoma

DOI:  https://doi.org/10.1016/j.ejphar.2024.176544
Sci Rep. 2024 03 26. 14(1): 7140

Camptothecin enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.

Hankang Wang, Congcong Gao, Xiaodong Li, Feng Chen, Guijie Li.

  Apatinib has been shown to apply to a variety of solid tumors, including advanced hepatocellular carcinoma. Preclinical and preliminary clinical results confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) inhibitors. In this study, we investigated camptothecin (CPT) enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma. CPT combined with a PD-1 inhibitor enhances the anti-tumor effects of low-dose apatinib in hepatocellular carcinoma which was evaluated in making use of the H22 mouse model (n = 32), which was divided into four groups. Immunohistochemical staining and western blotting were used to detect nuclear factor erythroid 2-related factor 2 (Nrf2) as well as sequestosome 1 (p62), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), PD-1, and programmed cell death ligand 1 (PD-L1). The results showed that the average size of the tumor of the combination group (Group D) was significantly less than that of the apatinib + PD-1 inhibitor group (Group C). The expression levels of Nrf2, p62, VEGFA, VEGFR2, PD-1, and PD-L1 in the apatinib + PD-1 inhibitor group(Group C) were lower than those in the control group (Group A) (P < 0.05). The expression levels of these genes in the apatinib + PD-1 inhibitor group (Group C) were significantly lower in the combination group (Group D) (P < 0.05). There was no obvious difference in body weight and liver and kidney functions between the four groups of mice. In conclusion, CPT improves the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.

Keywords:  Apatinib; Camptothecin; Hepatocellular carcinoma; Nrf2; PD-1 inhibitor

DOI:  https://doi.org/10.1038/s41598-024-57874-6
Cell Death Dis. 2024 Mar 23. 15(3): 233

AURKA emerges as a vulnerable target for KEAP1-deficient non-small cell lung cancer by activation of asparagine synthesis.

Bing Deng, Fang Liu, Nana Chen, Xinhao Li, Jie Lei, Ning Chen, Jingjing Wu, Xuan Wang, Jie Lu, Mouxiang Fang, Ailin Chen, Zijian Zhang, Bin He, Min Yan, Yuchen Zhang, Zifeng Wang, Quentin Liu.

AURKA is an established target for cancer therapy; however, the efficacy of its inhibitors in clinical trials is hindered by differential response rates across different tumor subtypes. In this study, we demonstrate AURKA regulates amino acid synthesis, rendering it a vulnerable target in KEAP1-deficient non-small cell lung cancer (NSCLC). Through CRISPR metabolic screens, we identified that KEAP1-knockdown cells showed the highest sensitivity to the AURKA inhibitor MLN8237. Subsequent investigations confirmed that KEAP1 deficiency heightens the susceptibility of NSCLC cells to AURKA inhibition both in vitro and in vivo, with the response depending on NRF2 activation. Mechanistically, AURKA interacts with the eIF2α kinase GCN2 and maintains its phosphorylation to regulate eIF2α-ATF4-mediated amino acid biosynthesis. AURKA inhibition restrains the expression of asparagine synthetase (ASNS), making KEAP1-deficient NSCLC cells vulnerable to AURKA inhibitors, in which ASNS is highly expressed. Our study unveils the pivotal role of AURKA in amino acid metabolism and identifies a specific metabolic indication for AURKA inhibitors. These findings also provide a novel clinical therapeutic target for KEAP1-mutant/deficient NSCLC, which is characterized by resistance to radiotherapy, chemotherapy, and targeted therapy.

DOI: https://doi.org/10.1038/s41419-024-06577-x
Cell Biochem Biophys. 2024 Mar 27.

Cell-Cycle-related Protein Centromere Protein F Deficiency Inhibits Cervical Cancer Cell Growth by Inducing Ferroptosis Via Nrf2 Inactivation.

Xin Hui Tang, Tian Nan Zhao, Li Guo, Xin Yue Liu, Wei Na Zhang, Ping Zhang.

  Cervical cancer (CC) is one of the severe cancers that pose a threat to women's health and result in death. CENPF, the centromere protein F, plays a crucial role in mitosis by regulating numerous cellular processes, such as chromosome segregation during mitosis. According to bioinformatics research, CENPF serves as a master regulator that is upregulated and activated in cervical cancer. Nevertheless, the precise biological mechanism that CENPF operates in CC remains unclear. The aim of this study was to analyze the function of CENPF on cervical cancer and its mechanism. We conducted immunohistochemistry and western blot analysis to examine the expression levels of CENPF in both cervical cancer tissues and cells. To explore the hidden biological function of CENPF in cell lines derived from CC, we applied lentivirus transfection to reduce CENPF manifestation. CENPF's main role is to regulate ferroptosis which was assessed by analyzing Reactive Oxygen Species (ROS), malonaldehyde (MDA), etc. The vitro findings were further validated through a subcutaneous tumorigenic nude mouse model. Our research finding indicates that there is an apparent upregulation of CENPF in not merely tumor tissues but also cell lines in the carcinomas of the cervix. In vitro and vivo experimental investigations have demonstrated that the suppression of CENPF can impede cellular multiplication, migration, and invasion while inducing ferroptosis. The ferroptosis induced by CENPF inhibition in cervical cancer cell lines is likely mediated through the Nrf2/HO-1 pathway. The data herein come up with the opinion that CENPF may have a crucial role in influencing anti-cervical cancer effects by inducing ferroptosis via the triggering of the Nrf2/HO-1 signaling pathway.

Keywords:  CENPF; Cell cycle; Cervical cancer; Ferroptosis; Nuclear factor E2-related factor 2

DOI:  https://doi.org/10.1007/s12013-024-01251-7
Antioxidants (Basel). 2024 Feb 27. pii: 291. [Epub ahead of print]13(3):

Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11.

Marilyn Mathew, Sathish Sivaprakasam, Gunadharini Dharmalingam-Nandagopal, Souad R Sennoune, Nhi T Nguyen, Valeria Jaramillo-Martinez, Yangzom D Bhutia, Vadivel Ganapathy.

  The amino acid transporters SLC38A5 and SLC7A11 are upregulated in triple-negative breast cancer (TNBC). SLC38A5 transports glutamine, methionine, glycine and serine, and therefore activates mTOR signaling and induces epigenetic modifications. SLC7A11 transports cystine and increases the cellular levels of glutathione, which protects against oxidative stress and lipid peroxidation via glutathione peroxidase, a seleno (Se)-enzyme. The primary source of Se is dietary Se-methionine (Se-Met). Since SLC38A5 transports methionine, we examined its role in Se-Met uptake in TNBC cells. We found that SLC38A5 interacts with methionine and Se-Met with comparable affinity. We also examined the influence of Se-Met on Nrf2 in TNBC cells. Se-Met activated Nrf2 and induced the expression of Nrf2-target genes, including SLC7A11. Our previous work discovered niclosamide, an antiparasitic drug, as a potent inhibitor of SLC38A5. Here, we found SLC7A11 to be inhibited by niclosamide with an IC50 value in the range of 0.1-0.2 μM. In addition to the direct inhibition of SLC38A5 and SLC7A11, the pretreatment of TNBC cells with niclosamide reduced the expression of both transporters. Niclosamide decreased the glutathione levels, inhibited proliferation, suppressed GPX4 expression, increased lipid peroxidation, and induced ferroptosis in TNBC cells. It also significantly reduced the growth of the TNBC cell line MB231 in mouse xenografts.

Keywords:  Nrf2; SLC38A5; SLC7A11; TNBC cells; ferroptosis; glutathione; glutathione peroxidase; lipid peroxidation; niclosamide; seleno-methionine

DOI:  https://doi.org/10.3390/antiox13030291
Cancer Lett. 2024 Mar 26. pii: S0304-3835(24)00226-X. [Epub ahead of print] 216833

IL-1α facilitates GSH synthesis to counteract oxidative stress in oral squamous cell carcinoma under glucose-deprivation.

Yikang Ji, Zhen Zhang, Xinran Zhao, Zhiyin Li, Xin Hu, Mi Zhang, Xinhua Pan, Xu Wang, Wantao Chen.

  Understanding the intrinsic mechanisms underpinning cancer metabolism and therapeutic resistance is of central importance for effective nutrition-starvation therapies. Here, we report that Interleukin 1A (IL1A) mRNA and IL-1α protein facilitate glutathione (GSH) synthesis to counteract oxidative stress and resistance against nutrition-starvation therapy in oral squamous cell carcinoma (OSCC). The expression of IL1A mRNA was elevated in the case of OSCC associated with unfavorable clinical outcomes. Both IL1A mRNA and IL-1α protein expression were increased under glucose-deprivation in vitro and in vivo. The transcription of IL1A mRNA was regulated in an NRF2-dependent manner in OSCC cell lines under glucose-deprivation. Moreover, the IL-1α conferred resistance to oxidative stress via GSH synthesis in OSCC cell lines. The intratumoral administration of siRNAs against IL1A mRNA markedly reversed GSH production and sensitized OSCC cells to Anlotinib in HN6 xenograft models. Overall, the current study demonstrates novel evidence that the autocrine IL-1α favors endogenous anti-oxidative process and confers therapeutic resistance to nutrition-starvation in OSCCs.

Keywords:  IL1A; NRF2; Nutrition starvation; OSCC; Oxidative stress

DOI:  https://doi.org/10.1016/j.canlet.2024.216833
Ann Hematol. 2024 Mar 27.

Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway.

Yu Zhang, Xiaoshun Wang, Xiaoqi Li, Xingfang Xiong, Renyu Xue, Lanlan Zang, Zhiqiang Wang, Lijuan Wang.

  Multiple myeloma (MM) is a common malignant hematologic neoplasm, and the involvement of epigenetic modifications in its development and drug resistance has received widespread attention. Ferroptosis, a new ferroptosis-dependent programmed death mode, is closely associated with the development of MM. The novel methyltransferase inhibitor DCG066 has higher cell activity, but its mechanism of action in MM has not been clarified. Here, we found that DCG066 (5µM) inhibited the proliferation and induced ferroptosis in MM cells; the intracellular levels of ROS, iron, and MDA were significantly elevated, and the level of GSH was reduced after the treatment of DCG066; The protein expression levels of SLC7A11, GPX4, Nrf2 and HO-1 were significantly reduced, and these phenomena could be reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ). Meanwhile, the protein expression levels of Keap1 was increased, and heat shock proteins (HSP70, HSP90 and HSPB1) were reduced after DCG066 treatment. In conclusion, this study confirmed that DCG066 inhibits MM proliferation and induces ferroptosis via the Nrf2/HO-1 pathway.

Keywords:  Ferroptosis; Histone methyltransferase G9a; Multiple myeloma; Nuclear factor E2-related factor 2; Proliferation

DOI:  https://doi.org/10.1007/s00277-024-05728-6