bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2022–11–13
six papers selected by
Caner Geyik, Istinye University
  1. Nuclear factor erythroid 2-related factor 2 and autophagy regulation in cancer development.
  2. Spatial Analysis of NQO1 in Non-Small Cell Lung Cancer Shows Its Expression Is Independent of NRF1 and NRF2 in the Tumor Microenvironment.
  3. NRF2 modulation in TRAMP mice: an in vivo model of prostate cancer.
  4. Taxifolin Prevents Cisplatin Nephrotoxicity by Modulating Nrf2/HO-1 Pathway and Mitigating Oxidative Stress and Inflammation in Mice.
  5. The RSL3 Induction of KLK Lung Adenocarcinoma Cell Ferroptosis by Inhibition of USP11 Activity and the NRF2-GSH Axis.
  6. Mechanisms of P-Glycoprotein Regulation Under Exogenous and Endogenous Oxidative Stress In Vitro.
  1. Biophys Rev. 2022 Oct;14(5): 1105-1107
    Nuclear factor erythroid 2-related factor 2 and autophagy regulation in cancer development.
    Waleska Dornas.
      Nuclear factor erythroid 2-related factor 2 (Nrf2) mitigates cell damage due to stress, environmental xenobiotics, and toxic chemicals. Nrf2 is present in the cytoplasm bound to its cysteine-rich Kelch domain-containing partner, Kelch-like ECH-associated protein 1 (Keap1), where is ubiquitinated and degraded. In addition to inducers that disrupt the Keap1-Nrf2 complex, defective autophagy has recently been shown to upregulate endogenous p62, which interacts with Keap1 triggering transcriptional activation of Nrf2 in several cancers. This regulation by Nrf2-dependent transactivation of cytoprotective genes needs to be validated by clinical trials in view of its persistent activation in a p62-dependent manner when there is deregulation of autophagy.
    DOI:  https://doi.org/10.1007/s12551-022-00992-0
  2. Biomolecules. 2022 Nov 08. pii: 1652. [Epub ahead of print]12(11):
    Spatial Analysis of NQO1 in Non-Small Cell Lung Cancer Shows Its Expression Is Independent of NRF1 and NRF2 in the Tumor Microenvironment.
    Boback Kaghazchi, In Hwa Um, Mustafa Elshani, Oliver J Read, David J Harrison.
      Nuclear factor erythroid 2-related factor 1 (NFE2L1, NRF1) and nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2) are distinct oxidative stress response transcription factors, both of which have been shown to perform cytoprotective functions, modulating cell stress response and homeostasis. NAD(P)H:quinone oxidoreductase (NQO1) is a mutual downstream antioxidant gene target that catalyzes the two-electron reduction of an array of substrates, protecting against reactive oxygen species (ROS) generation. NQO1 is upregulated in non-small cell lung cancer (NSCLC) and is proposed as a predictive biomarker and therapeutic target. Antioxidant protein expression of immune cells within the NSCLC tumor microenvironment (TME) remains undetermined and may affect immune cell effector functions and survival outcomes. Multiplex immunofluorescence was performed to examine the co-localization of NQO1, NRF1 and NRF2 within the tumor and TME of 162 chemotherapy-naïve, early-stage NSCLC patients treated by primary surgical resection. This study demonstrates that NQO1 protein expression is high in normal, tumor-adjacent tissue and that NQO1 expression varies depending on the cell type. Inter and intra-patient heterogenous NQO1 expression was observed in lung cancer. Co-expression analysis showed NQO1 is independent of NRF1 and NRF2 in tumors. Density-based co-expression analysis demonstrated NRF1 and NRF2 double-positive expression in cancer cells is associated with improved overall survival.
    Keywords:  non-small cell lung cancer; reactive oxygen species; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom12111652
  3. Mol Biol Rep. 2022 Nov 06.
    NRF2 modulation in TRAMP mice: an in vivo model of prostate cancer.
    Daniela Marzioni, Roberta Mazzucchelli, Sonia Fantone, Giovanni Tossetta.
       BACKGROUND: Prostate cancer (PCa) is one of the most common cancers worldwide and oxidative stress is involved in its occurrence, development and progression. In fact, in transgenic adenocarcinoma of mouse prostate (TRAMP) mice, prostate cancer onset is associated with the methylation of the first five CpG in the nuclear factor erythroid 2-related factor 2 (NRF2) promoter, a key regulator of oxidative stress response, leading to its downregulation and accumulation of reactive oxygen species (ROS). It has been demonstrated that both natural and synthetic compounds can reactivate NRF2 expression inhibiting the methylation status of its promoter by downregulation of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Interestingly, NRF2 re-expression significantly reduced prostate cancer onset in TRAMP mice highlighting an important role of NRF2 in prostate tumorigenesis.
    METHODS AND RESULTS: We analysed the current literature regarding the role of natural and synthetic compounds in modulating NRF2 pathway in TRAMP mice, an in vivo model of prostate cancer, to give an overview on prostate carcinogenesis and its possible prevention.
    CONCLUSION: We can conclude that specific natural and synthetic compounds can downregulate DNMTs and/or HDACs inhibiting the methylation status of NRF2 promoter, then reactivating the expression of NRF2 protecting normal prostatic cells from ROS damage and tumorigenesis.
    Keywords:  Carcinogenesis; Compounds; NRF2; Prostate cancer; Signaling; TRAMP mice
    DOI:  https://doi.org/10.1007/s11033-022-08052-2
  4. Pharmaceuticals (Basel). 2022 Oct 24. pii: 1310. [Epub ahead of print]15(11):
    Taxifolin Prevents Cisplatin Nephrotoxicity by Modulating Nrf2/HO-1 Pathway and Mitigating Oxidative Stress and Inflammation in Mice.
    Abdulkareem A Alanezi, Afaf F Almuqati, Manal A Alfwuaires, Fawaz Alasmari, Nader I Namazi, Osama Y Althunibat, Ayman M Mahmoud.
      Cisplatin (CIS) is an effective chemotherapeutic agent used in the treatment of several malignancies. The clinical use of CIS is associated with adverse effects, including acute kidney injury (AKI). Oxidative stress and inflammation are key events in the development of CIS-induced AKI. This study investigated the protective effect of taxifolin (TAX), a bioactive flavonoid with promising health-promoting properties, on CIS-induced nephrotoxicity in mice. TAX was orally given to mice for 10 days and a single dose of CIS was injected at day 7. Serum blood urea nitrogen (BUN) and creatinine were elevated, and multiple histopathological alterations were observed in the kidney of CIS-administered mice. CIS increased renal malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappaB (NF-κB) p65, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, and decreased cellular antioxidants in mice. TAX remarkably prevented kidney injury, ameliorated serum BUN and creatinine, and renal MDA, NO, NF-κB p65, and pro-inflammatory cytokines, and boosted antioxidant defenses in CIS-administered mice. TAX downregulated Bax and caspase-3, and upregulated Bcl-2. These effects were associated with upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase (HO)-1 activity in CIS-administered mice. In conclusion, TAX prevented CIS-induced AKI by mitigating tissue injury, oxidative stress, inflammation, and cell death. The protective efficacy of TAX was associated with the upregulation of Nrf2/HO-1 signaling.
    Keywords:  Nrf2; chemotherapy; flavonoids; kidney injury; oxidative stress
    DOI:  https://doi.org/10.3390/ph15111310
  5. Cancers (Basel). 2022 Oct 25. pii: 5233. [Epub ahead of print]14(21):
    The RSL3 Induction of KLK Lung Adenocarcinoma Cell Ferroptosis by Inhibition of USP11 Activity and the NRF2-GSH Axis.
    Wenlong Zhang, Xiaohe Li, Jiaqian Xu, Ying Wang, Zhengcao Xing, Shuming Hu, Qiuju Fan, Shaoyong Lu, Jinke Cheng, Jianmin Gu, Rong Cai.
      Antioxidant transcription factor NRF2 plays a pivotal role in cell ferroptosis. KLK lung adenocarcinoma (LUAD) is a specific molecular subtype of Kras-mutant LUAD. The activation of mutant Kras in combination with the inactivation of Lkb1 and Keap1 abnormally increases NRF2 expression, while high NRF2 confers KLK LUAD cell resistance to ferroptosis. This study assessed the inhibition of NRF2-GSH axis to sensitize a small molecule RSL3 to induce KLK LUAD cell ferroptosis and then explored the underlying molecular mechanisms. The data showed that the NRF2-GSH inhibition sensitized RSL3 induction of KLK LUAD cell ferroptosis in vitro, while RSL3 treatment reduced level of NRF2 protein in KLK LUAD during ferroptosis. Moreover, RSL3 treatment inhibited activity of the NRF2-GSH signaling during in KLK LUAD cell ferroptosis in vitro and in vivo. Mechanistically, the RSL3 reduction of NRF2 expression was through the promotion of NRF2 ubiquitination in KLK LUAD cells. In addition, RSL3 was able to directly bind to USP11, a recently identified de-ubiquitinase of NRF2, and inactivate USP11 protein to induce NRF2 protein ubiquitination and degradation in KLK LUAD cells. These data revealed a novel mechanism of RSL3 induction in KLK LUAD cell ferroptosis by suppression of the USP11-NRF2-GSH signaling. Future study will confirm RSL3 as a novel therapeutic approach in control of KLK lung adenocarcinoma.
    Keywords:  KLK LUAD; NRF2; RSL3; USP11; ferroptosis
    DOI:  https://doi.org/10.3390/cancers14215233
  6. Acta Naturae. 2022 Jul-Sep;14(3):14(3): 69-78
    Mechanisms of P-Glycoprotein Regulation Under Exogenous and Endogenous Oxidative Stress In Vitro.
    Yu V Abalenikhina, A V Shchulkin, P Yu Mylnikov, E D Rokunov, E N Yakusheva.
      We investigated the mechanisms of P-glycoprotein (P-gp) transporter regulation in Caco-2 cells under exogenous and endogenous oxidative stress (OS). Exogenous OS was modeled by exposure of the growth medium to hydrogen peroxide at concentrations of 0.1, 0.5, and 1 μM for 24 h or 10 μM for 72 h. Endogenous OS was modeled by incubating cells with DL-buthionine sulfoximine (BSO, gamma-glutamylcysteine synthetase inhibitor) at a concentration of 10, 50, and 100 μM for 24 h. The levels of intracellular reactive oxygen species (ROS) were assessed using MitoTracker Red CM-H2XRos fluorescent probes. Relative P-gp contents were analyzed using Western blot. Exogenous and endogenous OS was shown to increase relative to P-gp contents. An important role played by the Nrf2-Keap1 signaling pathway in increasing the P-gp contents under H2O2-induced exogenous OS was revealed using specific inhibitors. The transcription factor HIF1 is involved in the regulation of the P-gp levels under 24-hour exogenous OS, and the transcription factor CAR is involved in the regulation of transporter levels under 72-hour OS. All tested transcription factors and signaling pathways are involved in P-gp induction under endogenous OS. Most likely, this is associated with the bimodal effect of BSO on Pgp. On the one hand, BSO induces the development of OS; on the other, BSO, as a xenobiotic, is able to stimulate PXR and CAR, which, in turn, increase the P-gp contents.
    Keywords:  CAR; Caco-2 cell line; HIF1α; Nrf2; P-glycoprotein; PXR; Western blot; oxidative stress
    DOI:  https://doi.org/10.32607/actanaturae.11759
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