bims-nurfca 2023-07-02 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–07–02
nine papers selected by
Caner Geyik, Istinye University

Alkaloids as Natural NRF2 Inhibitors: Chemoprevention and Cytotoxic Action in Cancer.
Roles of NRF2 in DNA damage repair.
Nrf2 drives hepatocellular carcinoma progression through acetyl-CoA-mediated metabolic and epigenetic regulatory networks.
Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma.
c-Myc protects hepatocellular carcinoma cell from ferroptosis induced by glutamine deprivation via upregulating GOT1 and Nrf2.
PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis.
Reductive stress induced by NRF2/G6PD through glucose metabolic reprogramming promotes malignant transformation in Arsenite-exposed human keratinocytes.
Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia.
Phellodendronoside A Exerts Anticancer Effects Depending on Inducing Apoptosis Through ROS/Nrf2/Notch Pathway and Modulating Metabolite Profiles in Hepatocellular Carcinoma.

Pharmaceuticals (Basel). 2023 Jun 07. pii: 850. [Epub ahead of print]16(6):

Alkaloids as Natural NRF2 Inhibitors: Chemoprevention and Cytotoxic Action in Cancer.

Darinka Gjorgieva Ackova, Viktorija Maksimova, Katarina Smilkov, Brigitta Buttari, Marzia Arese, Luciano Saso.

  Being a controller of cytoprotective actions, inflammation, and mitochondrial function through participating in the regulation of multiple genes in response to stress-inducing endogenous or exogenous stressors, the transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is considered the main cellular defense mechanism to maintain redox balance at cellular and tissue level. While a transient activation of NRF2 protects normal cells under oxidative stress, the hyperactivation of NRF2 in cancer cells may help them to survive and to adapt under oxidative stress. This can be detrimental and related to cancer progression and chemotherapy resistance. Therefore, inhibition of NRF2 activity may be an effective approach for sensitizing cancer cells to anticancer therapy. In this review, we examine alkaloids as NRF2 inhibitors from natural origin, their effects on cancer therapy, and/or as sensitizers of cancer cells to anticancer chemotherapeutics, and their potential clinical applications. Alkaloids, as inhibitor of the NRF2/KEAP1 signaling pathway, can have direct (berberine, evodiamine, and diterpenic aconitine types of alkaloids) or indirect (trigonelline) therapeutic/preventive effects. The network linking alkaloid action with oxidative stress and NRF2 modulation may result in an increased NRF2 synthesis, nuclear translocation, as well in a downstream impact on the synthesis of endogenous antioxidants, effects strongly presumed to be the mechanism of action of alkaloids in inducing cancer cell death or promoting sensitivity of cancer cells to chemotherapeutic agents. In this regard, the identification of additional alkaloids targeting the NRF2 pathway is desirable and the information arising from clinical trials will reveal the potential of these compounds as a promising target for anticancer therapy.

Keywords:  NRF2 inhibitors; alkaloids; anticancer therapy; cancer; chemoprevention; plant bioactive compound

DOI:  https://doi.org/10.3390/ph16060850
Cell Oncol (Dordr). 2023 Jun 26.

Roles of NRF2 in DNA damage repair.

Jiale Li, Chang Xu, Qiang Liu.

   PURPOSE: The transcription factor NF-E2-related factor 2 (NRF2) is a master regulator widely involved in essential cellular functions such as DNA repair. By clarifying the upstream and downstream links of NRF2 to DNA damage repair, we hope that attention will be drawn to the utilization of NRF2 as a target for cancer therapy.
METHODS: Query and summarize relevant literature on the role of NRF2 in direct repair, BER, NER, MMR, HR, and NHEJ in pubmed. Make pictures of Roles of NRF2 in DNA Damage Repair and tables of antioxidant response elements (AREs) of DNA repair genes. Analyze the mutation frequency of NFE2L2 in different types of cancer using cBioPortal online tools. By using TCGA, GTEx and GO databases, analyze the correlation between NFE2L2 mutations and DNA repair systems as well as the degree of changes in DNA repair systems as malignant tumors progress.
RESULTS: NRF2 plays roles in maintaining the integrity of the genome by repairing DNA damage, regulating the cell cycle, and acting as an antioxidant. And, it possibly plays roles in double stranded break (DSB) pathway selection following ionizing radiation (IR) damage. Whether pathways such as RNA modification, ncRNA, and protein post-translational modification affect the regulation of NRF2 on DNA repair is still to be determined. The overall mutation frequency of the NFE2L2 gene in esophageal carcinoma, lung cancer, and penile cancer is the highest. Genes (50 of 58) that are negatively correlated with clinical staging are positively correlated with NFE2L2 mutations or NFE2L2 expression levels.
CONCLUSION: NRF2 participates in a variety of DNA repair pathways and plays important roles in maintaining genome stability. NRF2 is a potential target for cancer treatment.

Keywords:  Base excision repair; DNA repair; Homologous recombination; NRF2; Non-homologous end joining; Nucleotide excision repair

DOI:  https://doi.org/10.1007/s13402-023-00834-5
Mol Cancer Res. 2023 Jun 26. pii: MCR-22-0935. [Epub ahead of print]

Nrf2 drives hepatocellular carcinoma progression through acetyl-CoA-mediated metabolic and epigenetic regulatory networks.

Caixia Xi, Junfeng Pang, Amanda Barrett, Anatolij Horuzsko, Satyanarayana Ande, Nahid F Mivechi, Xingguo Zhu.

Correlations between the oxidative stress response and metabolic reprogramming have been observed during malignant tumor formation; however, the detailed mechanism remains elusive. The transcription factor Nrf2, a master regulator of the oxidative stress response, mediates metabolic reprogramming in multiple cancers. In a mouse model of hepatocellular carcinoma (HCC), through metabolic profiling, genome-wide gene expression, and chromatin structure analyses, we present new evidence showing that in addition to altering antioxidative stress response signaling, Nrf2 ablation impairs multiple metabolic pathways to reduce the generation of acetyl-CoA and suppress histone acetylation in tumors, but not in tumor-adjacent normal tissue. Nrf2 ablation and dysregulated histone acetylation impair transcription complex assembly on downstream target antioxidant and metabolic regulatory genes for expression regulation. Mechanistic studies indicate that the regulatory function of Nrf2 is low glucose dependent, the effect of which is demolished under energy refeeding. Together, our results implicate an unexpected effect of Nrf2 on acetyl-CoA generation, in addition to its classic antioxidative stress response regulatory activity, integrates metabolic and epigenetic programs to drive HCC progression. Implications: This study highlights that Nrf2 integrates metabolic and epigenetic regulatory networks to dictate tumor progression and that Nrf2 targeting is therapeutically exploitable in HCC treatment.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0935
Antioxidants (Basel). 2023 Jun 20. pii: 1313. [Epub ahead of print]12(6):

Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma.

Marie Angèle Cucci, Margherita Grattarola, Chiara Monge, Antonella Roetto, Giuseppina Barrera, Emilia Caputo, Chiara Dianzani, Stefania Pizzimenti.

  The use of specific inhibitors towards mutant BRAF (BRAFi) and MEK (MEKi) in BRAF-mutated patients has significantly improved progression-free and overall survival of metastatic melanoma patients. Nevertheless, half of the patients still develop resistance within the first year of therapy. Therefore, understanding the mechanisms of BRAFi/MEKi-acquired resistance has become a priority for researchers. Among others, oxidative stress-related mechanisms have emerged as a major force. The aim of this study was to evaluate the contribution of Nrf2, the master regulator of the cytoprotective and antioxidant response, in the BRAFi/MEKi acquired resistance of melanoma. Moreover, we investigated the mechanisms of its activity regulation and the possible cooperation with the oncogene YAP, which is also involved in chemoresistance. Taking advantage of established in vitro melanoma models resistant to BRAFi, MEKi, or dual resistance to BRAFi/MEKi, we demonstrated that Nrf2 was upregulated in melanoma cells resistant to targeted therapy at the post-translational level and that the deubiquitinase DUB3 participated in the control of the Nrf2 protein stability. Furthermore, we found that Nrf2 controlled the expression of YAP. Importantly, the inhibition of Nrf2, directly or through inhibition of DUB3, reverted the resistance to targeted therapies.

Keywords:  A375 cell line; BRAFi/MEKi; D4M cell line; DUB3; Nrf2; YAP; dabrafenib; melanoma; targeted therapy resistance; trametinib

DOI:  https://doi.org/10.3390/antiox12061313
Mol Biol Rep. 2023 Jun 26.

c-Myc protects hepatocellular carcinoma cell from ferroptosis induced by glutamine deprivation via upregulating GOT1 and Nrf2.

Yuxiang Zhao, Yue Wang, Zeyu Miao, Yan Liu, Qing Yang.

   BACKGROUND: Glutamine metabolism is critical for development of hepatocellular carcinoma (HCC), which makes it a novel promising treatment target. However, clinical evidence suggested glutamine withdrawal therapy does not achieved the desired tumor suppression. Therefore, it is valuable to investigate the survival mechanisms of tumors with glutamine deprivation.
METHODS: The HCC cells were cultured in glutamine-free medium or supplemented with glutamine metabolites or ferroptosis inhibitors. The parameters related to ferroptosis and the activity of GSH synthesis-related enzymes of the HCC cells were detected by corresponding kits. The expressions of glutamate oxaloacetate transaminase 1 (GOT1), c-Myc and Nrf2 were detected by western blot and qRT-PCR. The chromatin immunoprecipitation and luciferase reporter assays were performed to investigate the correlation between c-Myc and GOT1. The siRNAs of c-Myc and GOT1 were used to explore their roles in GSH (GSH) synthesis and ferroptosis in vitro and in vivo.
RESULTS: Glutamine deprivation-induced ferroptosis did not completely inhibit HCC cells proliferation. Glutamine deprivation activated the expression of c-Myc, which promoted the transcription of GOT1 and Nrf2, consequently maintaining the GSH synthesis and inhibiting ferroptosis. In addition, combined inhibition of GOT1 with glutamine deprivation could result in better inhibition of HCC in vitro and in vivo.
CONCLUSIONS: In our work, the results indicate that GOT1 induced by c-Myc may play an important role in combating ferroptosis due to glutamine deprivation, making it a significant target in glutamine withdrawal therapy. This study provides a theoretical foundation for the clinical targeted therapy for HCC.

Keywords:  Ferroptosis; GOT1; Glutamine deprivation; Hepatocellular carcinoma; c-Myc

DOI:  https://doi.org/10.1007/s11033-023-08495-1
J Immunother Cancer. 2023 Jun;pii: e006890. [Epub ahead of print]11(6):

PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis.

Zhe Wang, Ruolei Li, Niuniu Hou, Juliang Zhang, Ting Wang, Pengyu Fan, Cheng Ji, Bo Zhang, Liuyin Liu, Yaping Wang, Jing Kong, Qing Yao, Jie Duan, Ge Zhao, Rui Ling, Jian Zhang.

   BACKGROUND: As an emerging treatment strategy for triple-negative breast cancer (TNBC), immunotherapy acts in part by inducing ferroptosis. Recent studies have shown that protein arginine methyltransferase 5 (PRMT5) has distinct roles in immunotherapy among multiple cancers by modulating the tumor microenvironment. However, the role of PRMT5 during ferroptosis, especially for TNBC immunotherapy, is unclear.
METHODS: PRMT5 expression in TNBC was measured by IHC (immunohistochemistry) staining. To explore the function of PRMT5 in ferroptosis inducers and immunotherapy, functional experiments were conducted. A panel of biochemical assays was used to discover potential mechanisms.
RESULTS: PRMT5 promoted ferroptosis resistance in TNBC but impaired ferroptosis resistance in non-TNBC. Mechanistically, PRMT5 selectively methylated KEAP1 and thereby downregulated NRF2 and its downstream targets which can be divided into two groups: pro-ferroptosis and anti-ferroptosis. We found that the cellular ferrous level might be a critical factor in determining cell fate as NRF2 changes. In the context of higher ferrous concentrations in TNBC cells, PRMT5 inhibited the NRF2/HMOX1 pathway and slowed the import of ferrous. In addition, a high PRMT5 protein level indicated strong resistance of TNBC to immunotherapy, and PRMT5 inhibitors potentiated the therapeutic efficacy of immunotherapy.
CONCLUSIONS: Our results reveal that the activation of PRMT5 can modulate iron metabolism and drive resistance to ferroptosis inducers and immunotherapy. Accordingly, PRMT5 can be used as a target to change the immune resistance of TNBC.

Keywords:  Breast Neoplasms; Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2023-006890
Sci Total Environ. 2023 Jun 28. pii: S0048-9697(23)03830-5. [Epub ahead of print] 165207

Reductive stress induced by NRF2/G6PD through glucose metabolic reprogramming promotes malignant transformation in Arsenite-exposed human keratinocytes.

Qianlei Yang, Rui Yan, Jie Zhang, Ting Zhang, Qi Kong, Xiaoyun Zhang, Haixuan Xia, Aojun Ye, Xinhua Qiao, Koichi Kato, Chang Chen, Yan An.

  Our previous research found that the nuclear factor-E2-related factor 2 (NRF2) protein was sustained activated in malignant transformation of human keratinocyte (HaCaT cells) caused by NaAsO2, but the role of NRF2 in it remains unknown. In this study, malignant transformation of HaCaT cells and labeled HaCaT cells used to detect mitochondrial glutathione levels (Mito-Grx1-roGFP2 HaCaT cells) were induced by 1.0 μM NaAsO2. Redox levels were measured at passages 0, early stage (passages 1, 7, 14), later stage (passages 21, 28 and 35) of arsenite-treated HaCaT cells. Oxidative stress levels increased at early stage. The NRF2 pathway was sustained activated. Cells and mitochondrial reductive stress levels (GSH/GSSG and NADPH/NADP+) increased. The mitochondrial GSH/GSSG levels of Mito-Grx1-roGFP2 HaCaT cells also increased. The indicators of glucose metabolism glucose-6-phosphate, lactate and the glucose-6-phosphate dehydrogenase (G6PD) levels increased, however Acetyl-CoA level decreased. Expression levels of glucose metabolic enzymes increased. After transfection with NRF2 siRNA, the indicators of glucose metabolism were reversed. After transfection with NRF2 or G6PD siRNA, cells and mitochondrial reductive stress levels decreased and the malignant phenotype was reversed. In conclusion, oxidative stress occurred in the early stage and the NRF2 was sustained high expression. In the later stage, increased NRF2/G6PD through glucose metabolic reprogramming induced reductive stress, thereby leading to malignant transformation.

Keywords:  G6PD; Malignant transformation; NRF2; Reductive stress; Sodium arsenite

DOI:  https://doi.org/10.1016/j.scitotenv.2023.165207
Int J Mol Sci. 2023 Jun 19. pii: 10350. [Epub ahead of print]24(12):

Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia.

María Villa-Morales, Laura Pérez-Gómez, Eduardo Pérez-Gómez, Pilar López-Nieva, Pablo Fernández-Navarro, Javier Santos.

  The standard-of-care treatment of T-cell acute lymphoblastic leukaemia (T-ALL) with chemotherapy usually achieves reasonable rates of initial complete response. However, patients who relapse or do not respond to conventional therapy show dismal outcomes, with cure rates below 10% and limited therapeutic options. To ameliorate the clinical management of these patients, it is urgent to identify biomarkers able to predict their outcomes. In this work, we investigate whether NRF2 activation constitutes a biomarker with prognostic value in T-ALL. Using transcriptomic, genomic, and clinical data, we found that T-ALL patients with high NFE2L2 levels had shorter overall survival. Our results demonstrate that the PI3K-AKT-mTOR pathway is involved in the oncogenic signalling induced by NRF2 in T-ALL. Furthermore, T-ALL patients with high NFE2L2 levels displayed genetic programs of drug resistance that may be provided by NRF2-induced biosynthesis of glutathione. Altogether, our results indicate that high levels of NFE2L2 may be a predictive biomarker of poor treatment response in T-ALL patients, which would explain the poor prognosis associated with these patients. This enhanced understanding of NRF2 biology in T-ALL may allow a more refined stratification of patients and the proposal of targeted therapies, with the ultimate goal of improving the outcome of relapsed/refractory T-ALL patients.

Keywords:  NRF2 (nuclear factor erythroid 2-related factor 2); T-cell acute lymphoblastic leukaemia (T-ALL); prognostic biomarker

DOI:  https://doi.org/10.3390/ijms241210350
J Hepatocell Carcinoma. 2023 ;10 935-948

Phellodendronoside A Exerts Anticancer Effects Depending on Inducing Apoptosis Through ROS/Nrf2/Notch Pathway and Modulating Metabolite Profiles in Hepatocellular Carcinoma.

Yanpo Si, Chengcheng Hui, Tao Guo, Mengqi Liu, Xiaohui Chen, Chunhong Dong, Shuying Feng.

   Purpose: To reveal the potential mechanism of PDA on hepatocellular carcinoma SMMC-7721 cells in vitro.
Methods: The cytotoxic activity, colony formation, cell cycle distribution, apoptosis and their associated protein analysis, intracellular reactive oxygen species (ROS) and Ca2+ levels, proteins in Nrf2 and Ntoch pathways and metabolite profiles of PDA against hepatocellular carcinoma were investigated.
Results: PDA with cytotoxic activity inhibited cell proliferation and migration, increased intracellular ROS, Ca2+ levels and MCUR1 protein expression in a dose-dependent manner, caused cell cycle arrest in the S phase and induced apoptosis via adjusting the levels of Bcl-2, Bax, and Caspase 3 proteins, and inhibited the activation of Notch1, Jagged, Hes1, Nrf2 and HO-1 proteins. Metabonomics data showed that PDA significantly regulated 144 metabolite levels tend to be normal level, especially carnitine derivatives, bile acid metabolites associated with hepatocellular carcinoma, and mainly enriched in ABC transporter, arginine and proline metabolism, primary bile acid biosynthesis, Notch signaling pathway, etc, and proved that PDA markedly adjusted Notch signaling pathway.
Conclusion: PDA exhibited the proliferation inhibition of SMMC-7721 cells by inhibiting ROS/Nrf2/Notch signaling pathway and significantly affected the metabolic profile, suggesting PDA could be a potential therapeutic agent for patients with hepatocellular carcinoma.

Keywords:  acylcarnitine; apoptosis; bile acids; isoquinoline alkaloid; metabolomics

DOI:  https://doi.org/10.2147/JHC.S403630