bims-nurfca 2022-11-27 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2022–11–27
six papers selected by
Caner Geyik, Istinye University

Periplocin exerts antitumor activity by regulating Nrf2-mediated signaling pathway in gemcitabine-resistant pancreatic cancer cells.
Nuclear factor (erythroid-derived 2)-like 2 counter-regulates thymosin beta-4 expression and primary cilium formation for HeLa cervical cancer cell survival.
UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis.
Anticancer Effects of Thymoquinone through the Antioxidant Activity, Upregulation of Nrf2, and Downregulation of PD-L1 in Triple-Negative Breast Cancer Cells.
Nrf2 and its dependent autophagy activation cooperatively counteract ferroptosis to alleviate acute liver injury.
Rosmarinic Acid Prevents Cisplatin-Induced Liver and Kidney Injury by Inhibiting Inflammatory Responses and Enhancing Total Antioxidant Capacity, Thereby Activating the Nrf2 Signaling Pathway.

Biomed Pharmacother. 2022 Nov 21. pii: S0753-3322(22)01428-7. [Epub ahead of print]157 114039

Periplocin exerts antitumor activity by regulating Nrf2-mediated signaling pathway in gemcitabine-resistant pancreatic cancer cells.

Eun Seo Bae, Woong Sub Byun, Chae Won Ock, Won Kyung Kim, Hyen Joo Park, Sang Kook Lee.

  Although gemcitabine-based chemotherapy is common and effective for pancreatic cancer (PC), acquired drug resistance is one of the major reasons for treatment failure. Therefore, a novel therapeutic approach for gemcitabine-resistant PC is required. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oxidative stress-responsive transcription factor regulating antioxidant responses and plays a crucial role in chemoresistance. In the present study, the antitumor activity of periplocin, a natural cardiac glycoside, was evaluated in an established gemcitabine-resistant PC cell line (PANC-GR). Nrf2 was overexpressed in gemcitabine-resistant cells, and Nrf2 knockdown recovered gemcitabine sensitivity in PANC-GR cells. The antiproliferative activity of periplocin was highly associated with Nrf2 downregulation and Nrf2-mediated signaling pathways in PANC-GR cells. Periplocin also increased reactive oxygen species production inducing G0/G1 cell cycle arrest and apoptosis in PANC-GR cells. Periplocin and gemcitabine combined significantly inhibited tumor growth in a PANC-GR cells-implanted xenograft mouse model via Nrf2 downregulation. Overall, these findings suggest that periplocin might be a novel therapeutic agent against gemcitabine resistance, as it could recover sensitivity to gemcitabine by regulating Nrf2-mediated signaling pathways in gemcitabine-resistant PC cells.

Keywords:  Apoptosis; Gemcitabine resistance; Nuclear factor erythroid-2-related factor 2 (Nrf2); Pancreatic cancer cell; Periplocin

DOI:  https://doi.org/10.1016/j.biopha.2022.114039
Sci Rep. 2022 Nov 23. 12(1): 20170

Nuclear factor (erythroid-derived 2)-like 2 counter-regulates thymosin beta-4 expression and primary cilium formation for HeLa cervical cancer cell survival.

Jae-Wook Lee, Pham Xuan Thuy, Ja Hyun Koo, Eun-Yi Moon.

We investigated the function of thymosin beta-4 (TB4) expression and primary cilium (PC) formation via the underlying Nrf2-dependent mechanism for cervical cancer cell (CC) survival under conditions of serum deprivation (SD). TB4 silencing was achieved using RNA interference. The percentage of PC formation was analyzed by immunofluorescence staining. Nrf2 expression was modified by the preparation of stable Nrf2-knockdown cells with shNrf2 and the overexpression of Nrf2 with pcDNA-Nrf2 plasmids. Gene expression was measured using reverse-transcription PCR, Gaussia luciferase assay, and western blotting. Cell viability was assessed using the MTT assay or CellTiter Glo assay. Reactive oxygen species (ROS) were detected with flow cytometry. CCs incubated in SD without fetal bovine serum remained viable, and SD increased PC formation and TB4 transcription. CC viability was further decreased by treatment with ciliobrevin A to inhibit PC formation or TB4-siRNA. SD increased ROS, including H2O2. N-acetylcysteine inhibited ROS production following H2O2 treatment or SD, which also decreased PC formation and TB4 transcription. Meanwhile, H2O2 increased PC formation, which was attenuated in response to TB4 siRNA. Treatment with H2O2 increased Nrf2 expression, antioxidant responsive element (ARE) activity, and PC formation, which were inhibited by the Nrf2 inhibitor clobestasol propionate. Nrf2 knockdown via expression of Tet-On shNrf2 enhanced ROS production, leading to increased PC formation and decreased TB4 expression; these effects were counteracted by Nrf2 overexpression. Our data demonstrate that Nrf2 counter-regulates TB4 expression and PC formation for CC survival under conditions of SD, suggesting cervical CC survival could be upregulated by PC formation via Nrf2 activation and TB4 expression.

DOI: https://doi.org/10.1038/s41598-022-24596-6
J Exp Clin Cancer Res. 2022 Nov 24. 41(1): 330

UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis.

Liang Zhao, Min Kang, Xiaomeng Liu, Zhenran Wang, Yan Wang, Haiqiang Chen, Wenhui Liu, Shiqian Liu, Baibei Li, Chong Li, Antao Chang, Bo Tang.

   BACKGROUND: Glycolysis metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options. The ubiquitin-proteasome system facilitates the turnover of most intracellular proteins with E3 ligase conferring the target selection and specificity. Ubiquitin protein ligase E3 component N-recognin 7 (UBR7), among the least studied E3 ligases, recognizes its substrate through a plant homeodomain (PHD) finger. Here, we bring into focus on its suppressive role in glycolysis and HCC tumorigenesis, dependent on its E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine 120 (H2BK120ub).
METHODS: In this study, we carried out high-throughput RNAi screening to identify epigenetic candidates in regulating lactic acid and investigated its possible roles in HCC progression.
RESULTS: UBR7 loss promotes HCC tumorigenesis both in vitro and in vivo. UBR7 inhibits glycolysis by indirectly suppressing HK2 expression, a downstream target of Nrf2/Bach1 axis. Mechanically, UBR7 regulates H2BK120ub to bind to Keap1 promoter through H2BK120ub monoubiquitination, thereby modulating Keap1 expression and downstream Nrf2/Bach1/HK2 signaling. Pharmaceutical and genetic inhibition of glycolytic enzymes attenuate the promoting effect of UBR7 deficiency on tumor growth. In addition, methyltransferase ALKBH5, downregulated in HCC, regulated UBR7 expression in an m6A-dependent manner.
CONCLUSIONS: These results collectively establish UBR7 as a critical negative regulator of aerobic glycolysis and HCC tumorigenesis through regulation of the Keap1/Nrf2/Bach1/HK2 axis, providing a potential clinical and therapeutic target for the HCC treatment.

Keywords:  Glycolysis; Hepatocellular carcinoma; Keap1-Nrf2-Bach1 signaling; Monoubiquitination; UBR7

DOI:  https://doi.org/10.1186/s13046-022-02528-6
Nutrients. 2022 Nov 13. pii: 4787. [Epub ahead of print]14(22):

Anticancer Effects of Thymoquinone through the Antioxidant Activity, Upregulation of Nrf2, and Downregulation of PD-L1 in Triple-Negative Breast Cancer Cells.

Getinet M Adinew, Samia S Messeha, Equar Taka, Ramesh B Badisa, Karam F A Soliman.

  The variety of therapies available for treating and preventing triple-negative breast cancer (TNBC) is constrained by the absence of progesterone receptors, estrogen receptors, and human epidermal growth factor receptor 2. Nrf2 (nuclear factor-erythroid 2-related factor), and PD-L1 (program cell death ligand 1), a downstream signaling target, have a strong correlation to oxidative stress and inflammation, major factors in the development and progression of TNBC. In this study, the genetically distinct MDA-MB-231 and MDA-MB-468 TNBC cells were treated with the natural component thymoquinone (TQ). The results show that TQ exhibits considerable antioxidant activity and decreases the generation of H2O2, at the same time increasing catalase (CAT) activity, superoxide dismutase (SOD) enzyme, and glutathione (GSH). Additionally, the results show that TQ treatment increased the levels of the different genes involved in the oxidative stress-antioxidant defense system PRNP, NQO1, and GCLM in both cell lines with significant large-fold change in MDA-MB-468 cells (+157.65 vs. +1.7, +48.87 vs. +2.63 and +4.78 vs. +2.17), respectively. Nrf2 mRNA and protein expression were also significantly increased in TQ-treated TNBC cells despite being higher in MDA-MB-468 cells (6.67 vs. 4.06). Meanwhile, TQ administration increased mRNA levels while decreasing PD-L1 protein expression in both cell lines. In conclusion, TQ modifies the expression of multiple oxidative-stress-antioxidant system genes, ROS, antioxidant enzymes, Nrf2, and PD-L1 protein, pointing to the therapeutic potential and chemopreventive utilization of TQ in TNBC.

Keywords:  Nrf2; PD-L1; breast cancer; oxidative stress; thymoquinone; triple-negative breast cancer

DOI:  https://doi.org/10.3390/nu14224787
Pharmacol Res. 2022 Nov 18. pii: S1043-6618(22)00509-6. [Epub ahead of print] 106563

Nrf2 and its dependent autophagy activation cooperatively counteract ferroptosis to alleviate acute liver injury.

Jiawei Liu, Chao Huang, Jianming Liu, Chao Meng, Qi Gu, Xinyue Du, Minyu Yan, Yingjie Yu, Fanglan Liu, Chunhua Xia.

  Ferroptosis has been implicated in the pathophysiological progression of a variety of diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular antioxidant response and can counteract ferroptosis by inducing autophagy and targeting genes involved in iron metabolism and glutathione (GSH) synthesis/metabolism. This study investigated how Nrf2 and autophagy interact to prevent ferroptosis in acute liver injury under sulforaphane (SFN) intervention. The results showed that SFN could activate Nrf2 signaling pathway and its downstream target genes, promote cell autophagy, and then combat ferroptosis to alleviate liver injury. After inhibiting Nrf2, the autophagy activated by SFN almost disappeared, and the anti-ferroptosis effect was greatly weakened. After inhibiting autophagy, SFN can still activate Nrf2 and its downstream target gene, but solute carrier family 7 member 11 (SLC7A11) membrane transfer and its cystine transport ability are significantly weakened, thus ultimately attenuating the anti-ferroptosis effect of SFN. Further studies showed that Nrf2-dependent autophagy activation disrupted SLC7A11 binding to S93-phosphorylated coiled-coil myosin-like BCL2-interacting protein (BECN1) and increased SLC7A11 membrane transfer to combat ferroptosis. In conclusion, Nrf2-dependent autophagy activation is essential for promoting SLC7A11 membrane localization to inhibit ferroptosis. Activation of Nrf2 not only upregulates the expression of SLC7A11, glutathione peroxidase 4 (GPX-4) and autophagy-related proteins, but also destroys the binding of SLC7A11 and BECN1 by inducing autophagy, thereby promoting SLC7A11 membrane transfer and GSH synthesis, and finally suppressing ferroptosis. However, inhibition of autophagy had no significant effect on the expression of Nrf2 and downstream genes during SFN anti-liver injury intervention.

Keywords:  Acute liver injury; Autophagy; Ferroptosis; Nrf2; SLC7A11

DOI:  https://doi.org/10.1016/j.phrs.2022.106563
Molecules. 2022 Nov 13. pii: 7815. [Epub ahead of print]27(22):

Rosmarinic Acid Prevents Cisplatin-Induced Liver and Kidney Injury by Inhibiting Inflammatory Responses and Enhancing Total Antioxidant Capacity, Thereby Activating the Nrf2 Signaling Pathway.

Yifei Xiang, Min Ji, Liqin Wu, Li Lv, Qiuling Liang, Ruihan Deng, Zhaoyou Deng, Xia Liu, Lingyi Ren, Xin Feng, Jiakang He.

  Drug-induced liver and kidney damage is an emergent clinical issue that should be addressed. Rosmarinic acid (RA) has obvious anti-inflammatory and antioxidant effects, so we evaluated the anti-inflammatory and antioxidant effects of RA pretreatment on serum and liver and kidney tissues of cisplatin (CP)-treated mice and explored the possible mechanisms. The results showed that RA pretreatment effectively downregulated the serum, liver, and kidney levels of ALT, AST, BUN, and CRE and the inflammatory factors IL-1β, IL-6, and TNF-α, and simultaneously enhanced the total antioxidant capacity of the liver and kidney. RA pretreatment significantly reduced the levels of MPO, MDA, and NO in liver and kidney tissue, inhibited the mRNA expression of IL-1β, IL-6, and TNF-α in liver and kidney tissue, activated the Nrf2 signaling pathway, and upregulated the mRNA expression of downstream target genes. Our findings show that RA could effectively prevent and alleviate acute liver and kidney injury caused by CP.

Keywords:  Nrf2; acute liver and kidney injury; cisplatin; inflammation; oxidative stress; rosmarinic acid

DOI:  https://doi.org/10.3390/molecules27227815