bims-nurfca 2023-11-26 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–11–26
eight papers selected by
Caner Geyik, Istinye University

[Research Progress of Nrf2 and Ferroptosis in Tumor Drug Resistance].
Ovatodiolide induces autophagy-mediated cell death through the p62-Keap1-Nrf2 signaling pathway in chronic myeloid leukemia cells.
Loss of Nrf1 rather than Nrf2 leads to inflammatory accumulation of lipids and reactive oxygen species in human hepatoma cells, which is alleviated by 2-bromopalmitate.
The Important Role of Protein Kinases in the p53 Sestrin Signaling Pathway.
Adaptive changes in tumor cells in response to reductive stress.
Anticarcinogenic Potency of EF24: An Overview of Its Pharmacokinetics, Efficacy, Mechanism of Action, and Nanoformulation for Drug Delivery.
Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.
Metabolic and immune-related gene signatures: Predictive stratification and prognostic implications in gastric cancer.

Zhongguo Fei Ai Za Zhi. 2023 Oct 20. 26(10): 765-773

[Research Progress of Nrf2 and Ferroptosis in Tumor Drug Resistance].

Shuning Hu, Xinru Zou, Yixuan Fang, Chengrui Liu, Rui Chen, Lili Ji.

  Lung cancer is one of the most common cancers in the world, and its treatment strategy is mainly surgery combined with radiotherapy and chemotherapy. However, long-term chemotherapy will result in drug resistance, which is also one of the difficulties in the treatment of lung cancer. Ferroptosis is an iron-dependent and lipid peroxidation-driven non-apoptotic cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (Nrf2) is key for cellular antioxidant responses. Numerous studies suggest that Nrf2 assumes an extremely important role in regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. In this review, a brief overview of the research progress of ferroptosis over the past decade will be presented. In particular, the mechanism of ferroptosis and the regulation of ferroptosis by Nrf2 will be discussed, as well as the role of the Nrf2 pathway and ferroptosis in tumor drug resistance, which will provide new research directions for the treatment of drug-resistant lung cancer patients. .

Keywords:  Cancer; Drug resistance; Ferroptosis; Nrf2

DOI:  https://doi.org/10.3779/j.issn.1009-3419.2023.101.31
Chem Biol Interact. 2023 Nov 22. pii: S0009-2797(23)00486-6. [Epub ahead of print] 110819

Ovatodiolide induces autophagy-mediated cell death through the p62-Keap1-Nrf2 signaling pathway in chronic myeloid leukemia cells.

Qingqing Xia, Jing Xie, Jianguo Zhang, Lingmin Zhang, Yingying Zhou, Bihong Zhu, Yanfang Wu, Zaixing Yang, Jie Li.

  Ovatodiolide is a macrocyclic diterpenoid compound with various biological activities that displays considerable anticancer potential in different tumor models. However, the underlying mechanism for this antineoplastic activity remains unclear. The aim of the present study was to investigate the anticancer effect and possible molecular mechanism of ovatodiolide in human chronic myeloid leukemia (CML). Ovatodiolide suppressed cell colony formation and induced apoptosis in the K562 and KU812 cells. We also observed that ovatodiolide enhanced the production of reactive oxygen species (ROS), activated Nrf2 signaling, and inhibited mTOR phosphorylation. Autophagic flux was shown to be enhanced after treatment with ovatodiolide in K562 cells. Furthermore, autophagy inhibition alleviated ovatodiolide-induced cell apoptosis, whereas autophagy promotion aggravated apoptosis in CML cells. These results demonstrated that ovatodiolide activates autophagy-mediated cell death in CML cells. Additionally, ovatodiolide transcriptionally activated the expression of p62, and the p62 levels were negatively regulated by autophagy. Moreover, p62-Keap1-Nrf2 signaling was confirmed to be involved in ovatodiolide-induced cell death. Accordingly, LC3B knockdown augmented the ovatodiolide-induced p62 expression, increased the p62-Keap1 interaction, and enhanced the translocation of Nrf2 into the nucleus. In contrast, p62 inhibition abolished the effects that were induced through ovatodiolide treatment. Nrf2 inhibition with ML385 diminished the protective effect of autophagy inhibition in CML cells. Collectively, our results indicate that ovatodiolide induces oxidative stress and provokes autophagy, which effectively decreases the expression of p62 and weakens the protective effect of Nrf2 signaling activation, thus contributing to apoptosis in CML cells.

Keywords:  Autophagy; Autophagy-mediated cell death; Chronic myeloid leukemia; Ovatodiolide; p62-Keap1-Nrf2

DOI:  https://doi.org/10.1016/j.cbi.2023.110819
Biochim Biophys Acta Mol Cell Res. 2023 Nov 21. pii: S0167-4889(23)00217-3. [Epub ahead of print] 119644

Loss of Nrf1 rather than Nrf2 leads to inflammatory accumulation of lipids and reactive oxygen species in human hepatoma cells, which is alleviated by 2-bromopalmitate.

Rongzhen Deng, Ze Zheng, Shaofan Hu, Meng Wang, Jing Feng, Peter Mattjus, Zhengwen Zhang, Yiguo Zhang.

  Since Nrf1 and Nrf2 are essential for regulating the lipid metabolism pathways, their dysregulation has thus been shown to be critically involved in the non-controllable inflammatory transformation into cancer. Herein, we have explored the molecular mechanisms underlying their distinct regulation of lipid metabolism, by comparatively analyzing the changes in those lipid metabolism-related genes in Nrf1α-/- and/or Nrf2-/- cell lines relative to wild-type controls. The results revealed that loss of Nrf1α leads to lipid metabolism disorders. That is, its lipid synthesis pathway was up-regulated by the JNK-Nrf2-AP1 signaling, while its lipid decomposition pathway was down-regulated by the nuclear receptor PPAR-PGC1 signaling, thereby resulting in severe accumulation of lipids as deposited in lipid droplets. By contrast, knockout of Nrf2 gave rise to decreases in lipid synthesis and uptake capacity. These demonstrate that Nrf1 and Nrf2 contribute to significant differences in the cellular lipid metabolism profiles and relevant pathological responses. Further experimental evidence unraveled that lipid deposition in Nrf1α-/- cells resulted from CD36 up-regulation by activating the PI3K-AKT-mTOR pathway, leading to abnormal activation of the inflammatory response. This was also accompanied by a series of adverse consequences, e.g., accumulation of reactive oxygen species (ROS) in Nrf1α-/- cells. Interestingly, treatment of Nrf1α-/- cells with 2-bromopalmitate (2BP) enabled the yield of lipid droplets to be strikingly alleviated, as accompanied by substantial abolishment of CD36 and critical inflammatory cytokines. Such Nrf1α-/- led inflammatory accumulation of lipids, as well as ROS, was significantly ameliorated by 2BP. Overall, this study provides a potential strategy for cancer prevention and treatment by precision targeting of Nrf1, Nrf2 alone or both.

Keywords:  2-bromopalmitate (2BP); AP1; CD36; IL-6; JNK; Lipid droplets; Lipid metabolism; Nrf1; Nrf2; ROS; mTOR

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119644
Cancers (Basel). 2023 Nov 13. pii: 5390. [Epub ahead of print]15(22):

The Important Role of Protein Kinases in the p53 Sestrin Signaling Pathway.

Karsten Gülow, Deniz Tümen, Claudia Kunst.

  p53, a crucial tumor suppressor and transcription factor, plays a central role in the maintenance of genomic stability and the orchestration of cellular responses such as apoptosis, cell cycle arrest, and DNA repair in the face of various stresses. Sestrins, a group of evolutionarily conserved proteins, serve as pivotal mediators connecting p53 to kinase-regulated anti-stress responses, with Sestrin 2 being the most extensively studied member of this protein family. These responses involve the downregulation of cell proliferation, adaptation to shifts in nutrient availability, enhancement of antioxidant defenses, promotion of autophagy/mitophagy, and the clearing of misfolded proteins. Inhibition of the mTORC1 complex by Sestrins reduces cellular proliferation, while Sestrin-dependent activation of AMP-activated kinase (AMPK) and mTORC2 supports metabolic adaptation. Furthermore, Sestrin-induced AMPK and Unc-51-like protein kinase 1 (ULK1) activation regulates autophagy/mitophagy, facilitating the removal of damaged organelles. Moreover, AMPK and ULK1 are involved in adaptation to changing metabolic conditions. ULK1 stabilizes nuclear factor erythroid 2-related factor 2 (Nrf2), thereby activating antioxidative defenses. An understanding of the intricate network involving p53, Sestrins, and kinases holds significant potential for targeted therapeutic interventions, particularly in pathologies like cancer, where the regulatory pathways governed by p53 are often disrupted.

Keywords:  Sestrins; autophagy; mTORC; mitophagy; nuclear factor erythroid 2-related factor 2 (Nrf2); p53; stress response

DOI:  https://doi.org/10.3390/cancers15225390
Biochem Pharmacol. 2023 Nov 22. pii: S0006-2952(23)00522-1. [Epub ahead of print] 115929

Adaptive changes in tumor cells in response to reductive stress.

Leilei Zhang, Jie Zhang, Zhi-Wei Ye, Aslam Muhammad, Li Li, John W Culpepper, Danyelle M Townsend, Kenneth D Tew.

  Reductive stress is characterized by an excess of cellular electron donors and can be linked with various human pathologies including cancer. We developed melanoma cell lines resistant to reductive stress agents: rotenone (ROTR), n-acetyl-L-cysteine, (NACR), or dithiothreitol (DTTR). Resistant cells divided more rapidly and had intracellular homeostatic redox-couple ratios that were shifted towards the reduced state. Resistance caused alterations in general cell morphology, but only ROTR cells had significant changes in mitochondrial morphology with higher numbers that were more isolated, fragmented and swollen, with greater membrane depolarization and decreased numbers of networks. These changes were accompanied by lower basal oxygen consumption and maximal respiration rates. Whole cell flux analyses and mitochondrial function assays showed that NACR and DTTR preferentially utilized tricarboxylic acid (TCA) cycle intermediates, while ROTR used ketone body substrates such as D, L-β-hydroxybutyric acid. NACR and DTTR cells had constitutively decreased levels of reactive oxygen species (ROS), although this was accompanied by activation of nuclear factor erythroid 2-related factor 2 (Nrf2), with concomitant increased expression of the downstream gene products such as glutathione S-transferase P (GSTP). Further adaptations included enhanced expression of endoplasmic reticulum proteins controlling the unfolded protein response (UPR). Although expression patterns of these UPR proteins were distinct between the resistant cells, a trend implied that resistance to reductive stress is accompanied by a constitutively increased UPR phenotype in each line. Overall, tumor cells, although tolerant of oxidative stress, can adapt their energy and survival mechanisms in lethal reductive stress conditions.

Keywords:  Glycolysis; Melanoma cell lines; Mitochondrial morphology; Reactive oxygen species; Reductive stress; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bcp.2023.115929
Cancers (Basel). 2023 Nov 20. pii: 5478. [Epub ahead of print]15(22):

Anticarcinogenic Potency of EF24: An Overview of Its Pharmacokinetics, Efficacy, Mechanism of Action, and Nanoformulation for Drug Delivery.

Iliyana Sazdova, Milena Keremidarska-Markova, Daniela Dimitrova, Vadim Mitrokhin, Andre Kamkin, Nikola Hadzi-Petrushev, Jane Bogdanov, Rudolf Schubert, Hristo Gagov, Dimiter Avtanski, Mitko Mladenov.

  EF24, a synthetic monocarbonyl analog of curcumin, shows significant potential as an anticancer agent with both chemopreventive and chemotherapeutic properties. It exhibits rapid absorption, extensive tissue distribution, and efficient metabolism, ensuring optimal bioavailability and sustained exposure of the target tissues. The ability of EF24 to penetrate biological barriers and accumulate at tumor sites makes it advantageous for effective cancer treatment. Studies have demonstrated EF24's remarkable efficacy against various cancers, including breast, lung, prostate, colon, and pancreatic cancer. The unique mechanism of action of EF24 involves modulation of the nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, disrupting cancer-promoting inflammation and oxidative stress. EF24 inhibits tumor growth by inducing cell cycle arrest and apoptosis, mainly through inhibiting the NF-κB pathway and by regulating key genes by modulating microRNA (miRNA) expression or the proteasomal pathway. In summary, EF24 is a promising anticancer compound with a unique mechanism of action that makes it effective against various cancers. Its ability to enhance the effects of conventional therapies, coupled with improvements in drug delivery systems, could make it a valuable asset in cancer treatment. However, addressing its solubility and stability challenges will be crucial for its successful clinical application.

Keywords:  EF24; anticancer agent; curcumin; mechanism of action; nanoformulation; pharmacokinetics

DOI:  https://doi.org/10.3390/cancers15225478
bioRxiv. 2023 Nov 08. pii: 2023.11.06.565895. [Epub ahead of print]

Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.

Megan D Radyk, Barbara S Nelson, Christopher J Halbrook, Alexander Wood, Brooke Lavoie, Lucie Salvatore, Gabriel Corfas, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.

Activating mutations in KRAS extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS . The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of Kras G12D -driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant G6pd accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.

DOI: https://doi.org/10.1101/2023.11.06.565895
J Gene Med. 2023 Nov 20. e3635

Metabolic and immune-related gene signatures: Predictive stratification and prognostic implications in gastric cancer.

Jian Shao, Wenjia Zhang, Yiguang Li, Yi Tang, Lihong Fan.

   BACKGROUND: Gastric cancer, marked by its heterogeneous nature, showcases various molecular subtypes and clinical trajectories. This research delves into the significance of metabolic and immune-driven pathways in gastric cancer, constructing a prognostic signature derived from differentially expressed metabolic and immune-correlated genes (DE-MIGs).
METHODS: Metabolic and immune-associated gene were sourced from the GeneCards database. Differential expression analysis on the TCGA-STAD dataset was executed using the limma package, unveiling 51 DE-MIGs that underwent functional enrichment scrutiny. The LASSO Cox regression methodology guided the creation of the prognostic signature, and individual patient risk scores were determined. Assessment tools like CIBERSORT, ESTIMATE and ssGSEA were deployed to study the immune microenvironment, while mutation profiles, genomic stability, resistance to chemotherapy and immunotherapy responsiveness were scrutinized across distinct signature categorizations.
RESULTS: Among the identified DE-MIGs, 26 were significantly tied to the overall survival of gastric cancer patients. The developed prognostic signature proficiently differentiated patients into high-risk and low-risk cohorts, with the latter showing markedly better outcomes. The study underscored the centrality of the immune microenvironment in influencing gastric cancer outcomes. Key pathways such as TGF-Beta, TP53 and NRF2 dominated the high-risk group, whereas the LRTK-RAS and WNT pathways characterized the low-risk group. Interestingly, the low-risk segment also manifested a heightened tumor mutation burden and enhanced susceptibility to immunotherapy.
CONCLUSIONS: Our findings introduce a pivotal prognostic signature, rooted in DE-MIGs, that effectively segregates gastric cancer patients into distinct risk-based segments. Insights into the influential role of the immune microenvironment in gastric cancer progression pave the way for more refined therapeutic interventions.

Keywords:  gastric cancer; immunotherapy response; metabolic and immune signatures; prognostic stratification; tumor microenvironment

DOI:  https://doi.org/10.1002/jgm.3635