bims-nurfca 2024-03-03 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

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

Targeting Nrf2 to treat thyroid cancer.
Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer.
5-methylcytosine transferase NSUN2 drives NRF2-mediated ferroptosis resistance in non-small cell lung cancer.
Peiminine triggers ferroptosis to inhibit breast cancer growth through triggering Nrf2 signaling.
Aucubin alleviates doxorubicin-induced cardiotoxicity through crosstalk between NRF2 and HIPK2 mediating autophagy and apoptosis.
KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC.
APE1 inhibition enhances ferroptotic cell death and contributes to hepatocellular carcinoma therapy.
Therapeutic potential of dihydroartemisinin in mitigating radiation-induced lung injury: Inhibition of ferroptosis through Nrf2/HO-1 pathways in mice.
Vitamin C Inhibited Pulmonary Metastasis through Activating Nrf2/HO-1 Pathway.

Biomed Pharmacother. 2024 Feb 28. pii: S0753-3322(24)00205-1. [Epub ahead of print]173 116324

Targeting Nrf2 to treat thyroid cancer.

Zhongqin Gong, Lingbin Xue, Huangcan Li, Simiao Fan, Charles Andrew van Hasselt, Dongcai Li, Xianhai Zeng, Michael Chi Fai Tong, George Gong Chen.

  Oxidative stress (OS) is recognized as a contributing factor in the development and progression of thyroid cancer. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor involved in against OS generated by excessive reactive oxygen species (ROS). It governs the expression of a wide array of genes implicated in detoxification and antioxidant pathways. However, studies have demonstrated that the sustained activation of Nrf2 can contribute to tumor progression and drug resistance in cancers. The expression of Nrf2 was notably elevated in papillary thyroid cancer tissues compared to normal tissues, indicating that Nrf2 may play an oncogenic role in the development of papillary thyroid cancer. Nrf2 and its downstream targets are involved in the progression of thyroid cancer by impacting the prognosis and ferroptosis. Furthermore, the inhibition of Nrf2 can increase the sensitivity of target therapy in thyroid cancer. Therefore, Nrf2 appears to be a potential therapeutic target for the treatment of thyroid cancer. This review summarized current data on Nrf2 expression in thyroid cancer, discussed the function of Nrf2 in thyroid cancer, and analyzed various strategies to inhibit Nrf2.

Keywords:  Nrf2; Oxidative stress; Therapeutic; Thyroid cancer

DOI:  https://doi.org/10.1016/j.biopha.2024.116324
Exp Mol Med. 2024 Mar 01.

Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer.

Taegeun Bae, Steffanus Pranoto Hallis, Mi-Kyoung Kwak.

Oxygen is crucial for life and acts as the final electron acceptor in mitochondrial energy production. Cells adapt to varying oxygen levels through intricate response systems. Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, orchestrate the cellular hypoxic response, activating genes to increase the oxygen supply and reduce expenditure. Under conditions of excess oxygen and resulting oxidative stress, nuclear factor erythroid 2-related factor 2 (NRF2) activates hundreds of genes for oxidant removal and adaptive cell survival. Hypoxia and oxidative stress are core hallmarks of solid tumors and activated HIFs and NRF2 play pivotal roles in tumor growth and progression. The complex interplay between hypoxia and oxidative stress within the tumor microenvironment adds another layer of intricacy to the HIF and NRF2 signaling systems. This review aimed to elucidate the dynamic changes and functions of the HIF and NRF2 signaling pathways in response to conditions of hypoxia and oxidative stress, emphasizing their implications within the tumor milieu. Additionally, this review explored the elaborate interplay between HIFs and NRF2, providing insights into the significance of these interactions for the development of novel cancer treatment strategies.

DOI: https://doi.org/10.1038/s12276-024-01180-8
J Biol Chem. 2024 Feb 23. pii: S0021-9258(24)01266-3. [Epub ahead of print] 106793

5-methylcytosine transferase NSUN2 drives NRF2-mediated ferroptosis resistance in non-small cell lung cancer.

Youming Chen, Zuli Jiang, Chenxing Zhang, Lindong Zhang, Huanxiang Chen, Nan Xiao, Lu Bai, Hongyang Liu, Junhu Wan.

  RNA 5-methylcytosine (m5C) is an abundant chemical modification in mammalian RNAs and plays crucial roles in regulating vital physiological and pathological processes, especially in cancer. However, the dysregulation of m5C and its underlying mechanisms in non-small cell lung cancer (NSCLC) remain unclear. Here we identified that NSUN2, a key RNA m5C methyltransferase, is highly expressed in NSCLC tumor tissue. We found elevated NSUN2 expression levels strongly correlate with tumor grade and size, predicting poor outcomes for NSCLC patients. Furthermore, RNA-seq and subsequent confirmation studies revealed the antioxidant-promoting transcription factor NRF2 is a target of NSUN2, and depleting NSUN2 increases the sensitivity of NSCLC cells to ferroptosis activators both in vitro and in vivo. Additionally, knockdown of NSUN2 markedly inhibits the expression of NRF2 mRNA and protein. Intriguingly, the methylated-RIP-qPCR assay results indicated that NRF2 mRNA has a higher m5C level when NSUN2 is overexpressed in NSCLC cells, but shows no significant changes in the NSUN2 methyltransferase-deficient group. Mechanistically, we confirmed that NSUN2 upregulates the expression of NRF2 by enhancing the stability of NRF2 mRNA through the m5C modification within its 5'UTR region recognized by the specific m5C reader protein YBX1, rather than influencing its translation. In subsequent rescue experiments, we show knocking down NRF2 diminished the proliferation, migration, and ferroptosis tolerance mediated by NSUN2 overexpression. In conclusion, our study unveils a novel regulatory mechanism in which NSUN2 sustains NRF2 expression through an m5C-YBX1-axis, suggesting that targeting NSUN2 and its regulated ferroptosis pathway might offer promising therapeutic strategies for NSCLC patients.

Keywords:  NRF2; NSCLC; NSUN2; ferroptosis; m5C modification

DOI:  https://doi.org/10.1016/j.jbc.2024.106793
Tissue Cell. 2024 Feb 04. pii: S0040-8166(24)00024-7. [Epub ahead of print]87 102323

Peiminine triggers ferroptosis to inhibit breast cancer growth through triggering Nrf2 signaling.

Nian Yi, Li Wang, Zhongjun Jiang, Ge Xu, Lihong Li, Ya Zhang, Yinna Tan.

   BACKGROUND: Peiminine (PMI) is an active alkaloid sourced from Fritillaria thunbergii, which has been shown to suppress the development of a variety of tumors. Whereas, the roles and precise mechanism of PMI in breast cancer (BC) development remain not been clarified.
METHODS: The cytotoxic effect of PMI on MCF-10A and BC cell lines (MCF-7 and BT-549) were assessed by MTT and LDH release assay. Cell proliferation was evaluated by EdU staining. Levels of Malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH) activity and iron assay were measured by Enzyme linked immunosorbent assay (ELISA) kits, respectively. Transmission Electron Microscope was performed to observe mitochondrial morphological structure. Immunofluorescence, immunohistochemistry, and western blot were conducted to examine protein levels, respectively. Xenograft model was used to confirm cellular findings.
RESULTS: PMI treatment reduced the viability and enhanced LDH level of MCF-7 and BT-549 cells in a time- and concentration-dependent manner, and further suppressed cell proliferation in vitro and tumor growth in vivo. Subsequently, PMI administration resulted in significant increases of ROS, MDA and iron levels, reduction of GSH activity as well as mitochondrial shrinkage and GPX4 reduction, while all these phenomena could be rescued by ferrostatin-1. Mechanistically, PMI treatment led to promoted Nrf2 expression and its nuclear translocation, as well as it's downstream protein HO-1 and NQO1 expressions. Notably, ML-385, a Nrf2 specific inhibitor, greatly reversed the anti-tumor effects and pro-ferroptosis role of PMI in BC cells.
CONCLUSION: Taking these finding together, PMI could stimulate ferroptosis to inhibit BC tumor growth by activating Nrf2-HO-1 signaling pathway.

Keywords:  Breast cancer; Ferroptosis; Peiminine; Proliferation

DOI:  https://doi.org/10.1016/j.tice.2024.102323
Phytomedicine. 2024 Feb 21. pii: S0944-7113(24)00137-5. [Epub ahead of print]127 155473

Aucubin alleviates doxorubicin-induced cardiotoxicity through crosstalk between NRF2 and HIPK2 mediating autophagy and apoptosis.

Weili Li, Jing Cao, Yawen Zhang, Guanjing Ling, Nannan Tan, Yan Wei, Yuqin Zhang, Xiaoping Wang, Weina Qian, Jinchi Jiang, Jingmei Zhang, Wei Wang, Yong Wang.

   BACKGROUND: Doxorubicin (DOX) is widely used for the treatment of a variety of cancers. However, its clinical application is limited by dose-dependent cardiotoxicity. Recent findings demonstrated that autophagy inhibition and apoptosis of cardiomyocytes induced by oxidative stress dominate the pathophysiology of DOX-induced cardiotoxicity (DIC), however, there are no potential molecules targeting on these.
PURPOSE: This study aimed to explore whether aucubin (AU) acting on inimitable crosstalk between NRF2 and HIPK2 mediated the autophagy, oxidative stress, and apoptosis in DIC, and provide a new and alternative strategy for the treatment of DIC.
METHODS AND RESULTS: We first demonstrated the protection of AU on cardiac structure and function in DIC mice manifested by increased EF and FS values, decreased serum CK-MB and LDH contents and well-aligned cardiac tissue in HE staining. Furthermore, AU alleviated DOX-induced myocardial oxidative stress, mitochondrial damage, apoptosis, and autophagy flux dysregulation in mice, as measured by decreased ROS, 8-OHdG, and TUNEL-positive cells in myocardial tissue, increased SOD and decreased MDA in serum, aligned mitochondria with reduced vacuoles, and increased autophagosomes. In vitro, AU alleviated DOX-induced oxidative stress, autophagy inhibition, and apoptosis by promoting NRF2 and HIPK2 expression. We also identified crosstalk between NRF2 and HIPK2 in DIC as documented by overexpression of NRF2 or HIPK2 reversed cellular oxidative stress, autophagy blocking, and apoptosis aggravated by HIPK2 or NRF2 siRNA, respectively. Simultaneously, AU promoted the expression and nuclear localization of NRF2 protein, which was reversed by HIPK2 siRNA, and AU raised the expression of HIPK2 protein as well, which was reversed by NRF2 siRNA. Crucially, AU did not affect the antitumor activity of DOX against MCF-7 and HepG2 cells, which made up for the shortcomings of previous anti-DIC drugs.
CONCLUSION: These collective results innovatively documented that AU regulated the unique crosstalk between NRF2 and HIPK2 to coordinate oxidative stress, autophagy, and apoptosis against DIC without compromising the anti-tumor effect of DOX in vitro.

Keywords:  Aucubin; Autophagy; Cardiotoxicity; Doxorubicin; HIPK2; NRF2

DOI:  https://doi.org/10.1016/j.phymed.2024.155473
Cell Death Dis. 2024 Feb 27. 15(2): 175

KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC.

Jinghan Li, Daiwang Shi, Siyi Li, Xiang Shi, Yu Liu, Yi Zhang, Gebang Wang, Chenlei Zhang, Tian Xia, Hai-Long Piao, Hong-Xu Liu.

Immunotherapy has become a prominent first-line cancer treatment strategy. In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy. However, little is known about the regulation mechanism and the function of PD-L1 in lung cancer. In this study, we have discovered that KEAP1 serves as an E3 ligase to promote PD-L1 ubiquitination and degradation. We found that overexpression of KEAP1 suppressed tumor growth and promoted cytotoxic T-cell activation in vivo. These results indicate the important role of KEAP1 in anti-cancer immunity. Moreover, the combination of elevated KEAP1 expression with anti-PD-L1 immunotherapy resulted in a synergistic effect on both tumor growth and cytotoxic T-cell activation. Additionally, we found that the expressions of KEAP1 and PD-L1 were associated with NSCLC prognosis. In summary, our findings shed light on the mechanism of PD-L1 degradation and how NSCLC immune escape through KEAP1-PD-L1 signaling. Our results also suggest that KEAP1 agonist might be a potential clinical drug to boost anti-tumor immunity and improve immunotherapies in NSCLC.

DOI: https://doi.org/10.1038/s41419-024-06563-3
Cell Death Differ. 2024 Feb 28.

APE1 inhibition enhances ferroptotic cell death and contributes to hepatocellular carcinoma therapy.

Yu Du, Yu Zhou, Xinyu Yan, Feiyan Pan, Lingfeng He, Zhigang Guo, Zhigang Hu.

Ferroptosis, a regulated form of cell death triggered by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for cancer treatment, particularly in hepatocellular carcinoma (HCC). However, the mechanisms underlying the regulation of ferroptosis in HCC remain to be unclear. In this study, we have identified a novel regulatory pathway of ferroptosis involving the inhibition of Apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme with dual functions in DNA repair and redox regulation. Our findings demonstrate that inhibition of APE1 leads to the accumulation of lipid peroxidation and enhances ferroptosis in HCC. At the molecular level, the inhibition of APE1 enhances ferroptosis which relies on the redox activity of APE1 through the regulation of the NRF2/SLC7A11/GPX4 axis. We have identified that both genetic and chemical inhibition of APE1 increases AKT oxidation, resulting in an impairment of AKT phosphorylation and activation, which leads to the dephosphorylation and activation of GSK3β, facilitating the subsequent ubiquitin-proteasome-dependent degradation of NRF2. Consequently, the downregulation of NRF2 suppresses SLC7A11 and GPX4 expression, triggering ferroptosis in HCC cells and providing a potential therapeutic approach for ferroptosis-based therapy in HCC. Overall, our study uncovers a novel role and mechanism of APE1 in the regulation of ferroptosis and highlights the potential of targeting APE1 as a promising therapeutic strategy for HCC and other cancers.

DOI: https://doi.org/10.1038/s41418-024-01270-0
Immun Inflamm Dis. 2024 Feb;12(2): e1175

Therapeutic potential of dihydroartemisinin in mitigating radiation-induced lung injury: Inhibition of ferroptosis through Nrf2/HO-1 pathways in mice.

Xin Ning, Weidong Zhao, Qiaoyuan Wu, Cailan Wang, Shixiong Liang.

   BACKGROUND: Radiation-induced lung injury (RILI) is a common consequence of thoracic radiation therapy that lacks effective preventative and treatment strategies. Dihydroartemisinin (DHA), a derivative of artemisinin, affects oxidative stress, immunomodulation, and inflammation. It is uncertain whether DHA reduces RILI. In this work, we investigated the specific mechanisms of action of DHA in RILI.
METHODS: Twenty-four C57BL/6J mice were randomly divided into four groups of six mice each: Control group, irradiation (IR) group, IR + DHA group, and IR + DHA + Brusatol group. The IR group received no interventions along with radiation treatment. Mice were killed 30 days after the irradiation. Morphologic and pathologic changes in lung tissue were observed with hematoxylin and eosin staining. Detection of hydroxyproline levels for assessing the extent of pulmonary fibrosis. Tumor necrosis factor α (TNF-α), transforming growth factor-β (TGF-β), glutathione peroxidase (GPX4), Nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in lung tissues were detected. In addition, mitochondrial ultrastructural changes in lung tissues were also observed, and the glutathione (GSH) content in lung tissues was assessed.
RESULTS: DHA attenuated radiation-induced pathological lung injury and hydroxyproline levels. Additionally, it decreased TNF-α and TGF-β after irradiation. DHA may additionally stimulate the Nrf2/HO-1 pathway. DHA upregulated GPX4 and GSH levels and inhibited cellular ferroptosis. Brusatol reversed the inhibitory effect of DHA on ferroptosis and its protective effect on RILI.
CONCLUSION: DHA modulated the Nrf2/HO-1 pathway to prevent cellular ferroptosis, which reduced RILI. Therefore, DHA could be a potential drug for the treatment of RILI.

Keywords:  Nrf2/HO-1 pathways; dihydroartemisinin; ferroptosis; radiation-induced lung injury

DOI:  https://doi.org/10.1002/iid3.1175
Mol Nutr Food Res. 2024 Feb 28. e2300706

Vitamin C Inhibited Pulmonary Metastasis through Activating Nrf2/HO-1 Pathway.

Shuli Man, Jingxian Bi, Furui Liu, Wenwen Xie, Long Ma.

  As an important nutritional component, vitamin C (Vc) shows good antitumor activity in a variety of cancer, but there are few studies in pulmonary metastasis. In order to verify its anticancer and antimetastatic effect, the study sets up H22 pulmonary metastasis mouse model. The results show that intraperitoneal injection of Vc inhibits pulmonary metastasis through up-regulating the expression of Nrf2, HO-1, cleaved caspases 3 and 9, and causing DNA damage and apoptosis which is similar to the pro-oxidant effect of Vc in p53 null cells (H1299 cells). Meanwhile, oral administration of Vc up-regulates the expression of p53, directly activates Nrf2/HO-1 pathway, increases expression of cleaved caspases 3 and 9, and ultimately inhibits pulmonary metastasis, which is the same as the antioxidant result of Vc in p53 wild-type cells. In addition, Vc inhibits the proliferation and migration of lung cancer cells in a concentration-dependent manner and has little cytotoxic effects on normal cells. Notably, the experiment further illustrates that besides intravenous Vc, oral Vc significantly inhibits the pulmonary metastasis in mice. All in all, these findings provide new clues for Vc-treated pulmonary metastasis in clinical research.

Keywords:  DNA damage; Nrf2/HO-1; lung cancer; pulmonary metastasis; vitamin C

DOI:  https://doi.org/10.1002/mnfr.202300706