bims-nurfca 2023-12-24 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–12–24
ten papers selected by
Caner Geyik, Istinye University

Targeting Nrf2 Signaling Pathway in Cancer Prevention and Treatment: The Role of Cannabis Compounds.
Co-Delivery of siNRF2 and Sorafenib by a "Click" Dual Functioned Hyperbranched Nanocarrier for Synergistically Inducing Ferroptosis in Hepatocellular Carcinoma.
MiR-630 Promotes Radioresistance by Induction of Anti-Apoptotic Effect via Nrf2-GPX2 Molecular Axis in Head-Neck Cancer.
Acetyl barlerin from Barleria trispinosa induces chemopreventive NQO1 and attenuates LPS-induced inflammation: in vitro and molecular dynamic studies.
Flavonoids Regulate Redox-Responsive Transcription Factors in Glioblastoma and Microglia.
SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma.
Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia.
Aging-related NOX4-Nrf2 redox imbalance increases susceptibility to cisplatin-induced acute kidney injury by regulating mitophagy.
The Involvement of Peroxiporins and Antioxidant Transcription Factors in Breast Cancer Therapy Resistance.
Whole-transcriptome defines novel glucose metabolic subtypes in colorectal cancer.

Antioxidants (Basel). 2023 Nov 28. pii: 2052. [Epub ahead of print]12(12):

Targeting Nrf2 Signaling Pathway in Cancer Prevention and Treatment: The Role of Cannabis Compounds.

Anna Rybarczyk, Aleksandra Majchrzak-Celińska, Violetta Krajka-Kuźniak.

  The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, regulates the cellular defense against oxidative stress and inflammation, making it a promising cancer prevention and treatment target. Cannabinoids have demonstrated anti-tumor and anti-inflammatory properties, affecting signaling pathways, including Nrf2. Increased oxidative stress following exposure to anti-cancer therapy prompts cancer cells to activate antioxidant mechanisms. This indicates the dual effect of Nrf2 in cancer cells-influencing proliferation and apoptotic processes and protecting against the toxicity of anti-cancer therapy. Therefore, understanding the complex role of cannabinoids in modulating Nrf2 might shed light on its potential implementation as an anti-cancer support. In this review, we aim to highlight the impact of cannabinoids on Nrf2-related factors, with a focus on cancer prevention and treatment. Additionally, we have presented the results of several research studies that combined cannabidiol (CBD) with other compounds targeting Nrf2. Further studies should be directed toward exploring the anti-inflammatory effects of cannabinoids in the context of cancer prevention and therapy.

Keywords:  cancer; cannabidiol (CBD); cannabinoids; inflammation; nuclear factor erythroid 2-related factor 2 (Nrf2); oxidative stress

DOI:  https://doi.org/10.3390/antiox12122052
Small. 2023 Dec 15. e2307273

Co-Delivery of siNRF2 and Sorafenib by a "Click" Dual Functioned Hyperbranched Nanocarrier for Synergistically Inducing Ferroptosis in Hepatocellular Carcinoma.

Rongliang Tong, Xiaode Feng, Jingqi Sun, Zhenan Ling, Jun Wang, Shun Li, Beng Yang, Junfang Deng, Guijin He, Jian Wu.

  In the course of antitumor therapy, the complex tumor microenvironment and drug-mediated changes in cell signaling and biological processes lead to drug resistance. The effect of sorafenib is greatly limited by the specific tumor microenvironment induced by antiangiogenic therapy and ferroptosis resistance induced by the upregulation of nuclear factor erythroid-2 related factor 2 (NRF2). In this study, a pH responsive and amphiphilic hyperbranched polyglycerol, HDP, is synthesized based on a co-graft click chemistry pathway. This nano-scale carrier provides excellent drug-loading capacity, storing stability and pH responsibility, and effectively co-delivery of sorafenib and siRNA. Sorafenib and siNRF2 plays a greatly synergistic effect in inducing reactive oxygen species (ROS), iron overloading, depleting glutathione (GSH), and promoting lipid peroxidation. Importantly, verified in two different animal experiments, HDP-ss (HDP loaded with both siNRF2 and sorafenib) presents a superior anti-tumor effect, by achieving a tumor inhibition rate of ≈94%. Thus, HDP can serve as an excellent targeted delivery nanocarrier with good biocompatibility in antitumor therapy, and combined application of siNRF2 effectively improves the antitumor effect of sorafenib by overcoming NRF2-mediated ferroptosis resistance. Taken together, this study provides a novel therapeutic strategy to combat the drug resistance in antiangiogenic therapy and ferroptosis.

Keywords:  RNAi therapy; drug resistance; ferroptosis; hyperbranched polyglycerol; synergistic therapy

DOI:  https://doi.org/10.1002/smll.202307273
Cells. 2023 Dec 17. pii: 2853. [Epub ahead of print]12(24):

MiR-630 Promotes Radioresistance by Induction of Anti-Apoptotic Effect via Nrf2-GPX2 Molecular Axis in Head-Neck Cancer.

Guo-Rung You, Ann-Joy Cheng, Eric Yi-Liang Shen, Kang-Hsing Fan, Yi-Fang Huang, Yu-Chen Huang, Kai-Ping Chang, Joseph T Chang.

  Head and neck cancer (HNC) ranks among the top ten prevalent cancers worldwide. Radiotherapy stands as a pivotal treatment component for HNC; however, radioresistance in cancerous cells often leads to local recurrence, becoming a substantial factor in treatment failure. MicroRNAs (miRNAs) are compact, non-coding RNAs that regulate gene expression by targeting mRNAs to inhibit protein translation. Although several studies have indicated that the dysregulation of miRNAs is intricately linked with malignant transformation, understanding this molecular family's role in radioresistance remains limited. This study determined the role of miR-630 in regulating radiosensitivity in HNC. We discovered that miR-630 functions as an oncomiR, marked by its overexpression in HNC patients, correlating with a poorer prognosis. We further delineated the malignant function of miR-630 in HNC cells. While it had a minimal impact on cell growth, the miR-630 contributed to radioresistance in HNC cells. This result was supported by decreased cellular apoptosis and caspase enzyme activities. Moreover, miR-630 overexpression mitigated irradiation-induced DNA damage, evidenced by the reduced levels of the γ-H2AX histone protein, a marker for double-strand DNA breaks. Mechanistically, the overexpression of miR-630 decreased the cellular ROS levels and initiated Nrf2 transcriptional activity, resulting in the upregulation of the antioxidant enzyme GPX2. Thus, this study elucidates that miR-630 augments radioresistance by inducing an anti-apoptotic effect via the Nrf2-GPX2 molecular axis in HNC. The modulation of miR-630 may serve as a novel radiosensitizing target for HNC.

Keywords:  GPX2; Nrf2; apoptosis; head and neck cancer (HNC); miR-630; radioresistance

DOI:  https://doi.org/10.3390/cells12242853
J Biomol Struct Dyn. 2023 Dec 20. 1-12

Acetyl barlerin from Barleria trispinosa induces chemopreventive NQO1 and attenuates LPS-induced inflammation: in vitro and molecular dynamic studies.

Hamza M Assiry, Ahmed R Hamed, Gamal A Mohamed, Sabrin R M Ibrahim, Abdulrahman E Koshak, Azizah M Malebari, Sana A Fadil, Hossam M Abdallah.

  Extraction and fractionation of Barleria trispinosa growing in Saudi Arabia yielded four iridoid compounds identified by spectroscopic techniques as acetylbarlerin (1), barlerin (2), shanzhiside methyl ester (3) and 6-⍺-L-rhamnopyranosyl-8-O-acetylshanzihiside methyl ester (4). Preliminary experiments confirmed that compound 1 acts as an inducer of chemopreventive NAD(P)H:Quinone oxidoreductase 1 (NQO1) enzymatic activity in a murine hepatoma (Hepa1c1c7) chemoprevention model. It also demonstrated the ability to inhibit the lipopolysaccharides (LPS)-induced nitric oxide (NO) production in the RAW264.7 macrophage model. Western blotting revealed the ability of compound 1 to up-regulate the protein expression of the NQO1 marker. Furthermore, compound 1 elicited NO suppression in RAW264.7 macrophages by inhibiting iNOS protein expression. Molecular docking and molecular simulation studies of 1 supported its experimental results as an inhibitor of the nuclear factor erythroid 2-Kelch-like ECH-associated protein 1 (Nrf2-KEAP1) complex, resulting in Nrf2-mediated induction of chemopreventive NQO1.Communicated by Ramaswamy H. Sarma.

Keywords:  Barleria trispinosa; NAD(P)H:Quinone oxidoreductase 1; Nrf2-KEAP1; acetylbarlerin; industrial development

DOI:  https://doi.org/10.1080/07391102.2023.2293272
Cells. 2023 Dec 12. pii: 2821. [Epub ahead of print]12(24):

Flavonoids Regulate Redox-Responsive Transcription Factors in Glioblastoma and Microglia.

Natali Joma, Issan Zhang, Germanna L Righetto, Laura McKay, Evan Rizzel Gran, Ashok Kakkar, Dusica Maysinger.

  The tumor microenvironment (TME) has emerged as a valuable therapeutic target in glioblastoma (GBM), as it promotes tumorigenesis via an increased production of reactive oxygen species (ROS). Immune cells such as microglia accumulate near the tumor and its hypoxic core, fostering tumor proliferation and angiogenesis. In this study, we explored the therapeutic potential of natural polyphenols with antioxidant and anti-inflammatory properties. Notably, flavonoids, including fisetin and quercetin, can protect non-cancerous cells while eliminating transformed cells (2D cultures and 3D tumoroids). We tested the hypothesis that fisetin and quercetin are modulators of redox-responsive transcription factors, for which subcellular location plays a critical role. To investigate the sites of interaction between natural compounds and stress-responsive transcription factors, we combined molecular docking with experimental methods employing proximity ligation assays. Our findings reveal that fisetin decreased cytosolic acetylated high mobility group box 1 (acHMGB1) and increased transcription factor EB (TFEB) abundance in microglia but not in GBM. Moreover, our results suggest that the most powerful modulator of the Nrf2-KEAP1 complex is fisetin. This finding is in line with molecular modeling and calculated binding properties between fisetin and Nrf2-KEAP1, which indicated more sites of interactions and stronger binding affinities than quercetin.

Keywords:  fisetin; glioblastoma; microglia; natural polyphenols; oxidative stress; quercetin; reactive oxygen species; redox-responsive transcription factors; tumor microenvironment

DOI:  https://doi.org/10.3390/cells12242821
bioRxiv. 2023 Dec 15. pii: 2023.12.07.570642. [Epub ahead of print]

SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma.

Brianna R Daley, Nancy E Sealover, Erin Sheffels, Jacob M Hughes, Daniel Gerlach, Marco H Hofmann, Kaja Kostyrko, Barbara Mair, Amanda Linke, Zaria Beckley, Andrew Frank, Clifton L Dalgard, Robert L Kortum.

Clinical effectiveness of KRAS G12C inhibitors (G12Cis) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. We found that targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 both enhanced the potency of and delayed resistance to G12Ci treatment, but the extent of SOS1i effectiveness was modulated by both SOS2 expression and the specific mutational landscape. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. Survival of drug-tolerant persister (DTP) cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) that drive therapeutic resistance. G12Ci drug tolerant persister cells showed a 2-3-fold enrichment of TICs, suggesting that these could be a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor KEAP1 limits the clinical effectiveness of G12Cis, and KEAP1 and STK11 deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ci in situ. SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. These data suggest that SOS1i could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations.

DOI: https://doi.org/10.1101/2023.12.07.570642
Anesth Analg. 2023 Dec 18.

Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia.

Hee Kee Kim, Qi Wang, Seon-Hee Hwang, Patrick M Dougherty, Jing Wang, Salahadin Abdi.

BACKGROUND: Many chemotherapeutic drugs, including paclitaxel, produce neuropathic pain in patients with cancer, which is a dose-dependent adverse effect. Such chemotherapy-induced neuropathic pain (CINP) is difficult to treat with existing drugs. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidative responses and activates phosphorylated Nrf2 (pNrf2). We determined the analgesic effects of bardoxolone methyl (BM), an Nrf2 activator, and the role of pNrf2 on CINP.
METHODS: CINP was induced in rats by intraperitoneally injecting paclitaxel on 4 alternate days in rats. BM was injected systemically as single or repeated injections after pain fully developed. RNA transcriptome, mechanical hyperalgesia, levels of inflammatory mediators and pNrf2, and location of pNrf2 in the dorsal root ganglia (DRG) were measured by RNA sequencing, von Frey filaments, Western blotting, and immunohistochemistry in rats and human DRG samples. In addition, the mitochondrial functions in 50B11 DRG neuronal cells were measured by fluorescence assay.
RESULTS: Our RNA transcriptome of CINP rats showed a downregulated Nrf2 pathway in the pain condition. Importantly, single and repeated systemic injections of BM ameliorated CINP. Paclitaxel increased inflammatory mediators, but BM decreased them and increased pNrf2 in the DRG. In addition, paclitaxel decreased mitochondrial membrane potential and increased mitochondrial volume in 50B11 cells, but BM restored them. Furthermore, pNrf2 was expressed in neurons and satellite cells in rat and human DRG.
CONCLUSIONS: Our results demonstrate the analgesic effects of BM by Nrf2 activation and the fundamental role of pNrf2 on CINP, suggesting a target for CINP and a therapeutic strategy for patients.

DOI: https://doi.org/10.1213/ANE.0000000000006736
Life Sci. 2024 Jan 01. pii: S0024-3205(23)00987-6. [Epub ahead of print]336 122352

Aging-related NOX4-Nrf2 redox imbalance increases susceptibility to cisplatin-induced acute kidney injury by regulating mitophagy.

Jianqiang Hu, Wenli Hou, Ning Ma, Yan Zhang, Xiaojie Liu, Yuantao Wang, Xinxin Ci.

   BACKGROUND: During aging, excessive ROS production in the kidneys leads to redox imbalance, which contributes to oxidative damage and impaired organ homeostasis. However, whether and how aging-related NOX4-Nrf2 redox imbalance increases susceptibility to cisplatin-induced acute kidney injury remain largely unknown.
METHODS: In this study, we used cisplatin-challenged aging mouse models and senescent HK-2 cells to investigate the effects and mechanisms of aging on susceptibility to cisplatin-induced acute kidney injury.
RESULTS: In vivo, we found that cisplatin stimulation caused more severe renal damage, oxidative stress, mitochondrial dysfunction and mitophagy impairment in aging mice than in young mice. Moreover, Nrf2 deficiency aggravated cisplatin-induced acute kidney injury by exacerbating NOX4-Nrf2 redox imbalance and defective mitophagy. In vitro experiments on D-gal-treated human renal tubular epithelial cells (HK-2) demonstrated that senescent renal epithelial cells exhibited increased susceptibility to cisplatin-induced apoptosis, NOX4-Nrf2 redox imbalance-mediated oxidative stress and defective mitophagy. Mechanistically, we found that knockdown of Nrf2 in HK2 cells resulted in increased ROS and aggravated mitophagy impairment, whereas these effects were reversed in NOX4-knockdown cells.
CONCLUSION: The present study indicates that NOX4-Nrf2 redox imbalance is critical for mitophagy deficiency in aged renal tubular epithelial cells and is a therapeutic target for alleviating cisplatin-induced acute kidney injury in elderly patients.

Keywords:  Aging; Kidney; Mitophagy; Nrf2; Redox imbalance

DOI:  https://doi.org/10.1016/j.lfs.2023.122352
Cancers (Basel). 2023 Dec 08. pii: 5747. [Epub ahead of print]15(24):

The Involvement of Peroxiporins and Antioxidant Transcription Factors in Breast Cancer Therapy Resistance.

Lidija Milković, Monika Mlinarić, Ivan Lučić, Ana Čipak Gašparović.

  Breast cancer is still the leading cause of death in women of all ages. The reason for this is therapy resistance, which leads to the progression of the disease and the formation of metastases. Multidrug resistance (MDR) is a multifactorial process that leads to therapy failure. MDR involves multiple processes and many signaling pathways that support each other, making it difficult to overcome once established. Here, we discuss cellular-oxidative-stress-modulating factors focusing on transcription factors NRF2, FOXO family, and peroxiporins, as well as their possible contribution to MDR. This is significant because oxidative stress is a consequence of radiotherapy, chemotherapy, and immunotherapy, and the activation of detoxification pathways could modulate the cellular response to therapy and could support MDR. These proteins are not directly responsible for MDR, but they support the survival of cancer cells under stress conditions.

Keywords:  FOXO; NRF2; aquaporin; peroxiporin

DOI:  https://doi.org/10.3390/cancers15245747
J Cell Mol Med. 2023 Dec 20.

Whole-transcriptome defines novel glucose metabolic subtypes in colorectal cancer.

Shaohua Li, Wei Fang, Jianfeng Zheng, Zhiqiang Peng, Biyue Yu, Chunhui Chen, Yuting Zhang, Wenli Jiang, Shuhui Yuan, Lingqiang Zhang, Xueli Zhang.

  Colorectal cancer (CRC) is the most prevalent malignancy of the digestive system. Glucose metabolism plays a crucial role in CRC development. However, the heterogeneity of glucose metabolic patterns in CRC is not well characterized. Here, we classified CRC into specific glucose metabolic subtypes and identified the key regulators. 2228 carbohydrate metabolism-related genes were screened out from the GeneCards database, 202 of them were identified as prognosis genes in the TCGA database. Based on the expression patterns of the 202 genes, three metabolic subtypes were obtained by the non-negative matrix factorization clustering method. The C1 subtype had the worst survival outcome and was characterized with higher immune cell infiltration and more activation in extracellular matrix pathways than the other two subtypes. The C2 subtype was the most prevalent in CRC and was characterized by low immune cell infiltration. The C3 subtype had the smallest number of individuals and had a better prognosis, with higher levels of NRF2 and TP53 pathway expression. Secreted frizzled-related protein 2 (SFRP2) and thrombospondin-2 (THBS2) were confirmed as biomarkers for the C1 subtype. Their expression levels were elevated in high glucose condition, while their knockdown inhibited migration and invasion of HCT 116 cells. The analysis of therapeutic potential found that the C1 subtype was more sensitive to immune and PI3K-Akt pathway inhibitors than the other subtypes. To sum up, this study revealed a novel glucose-related CRC subtype, characterized by SFRP2 and THBS2, with poor prognosis but possible therapeutic benefits from immune and targeted therapies.

Keywords:  CRC; SFRP2; THBS2; glucose; immune therapies; molecular subtype

DOI:  https://doi.org/10.1111/jcmm.18065