bims-nurfca 2022-12-25 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2022–12–25
ten papers selected by
Caner Geyik, Istinye University

Nuclear factor Nrf2 promotes glycosidase OGG1 expression by activating the AKT pathway to enhance leukemia cell resistance to cytarabine.
Blockage of Nrf2 and autophagy by L-selenocystine induces selective death in Nrf2-addicted colorectal cancer cells through p62-Keap-1-Nrf2 axis.
Sulforaphane attenuates cancer cell-induced atrophy of C2C12 myotubes.
A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations.
Elevation of Anticancer Drug Toxicity by Caffeine in Spheroid Model of Human Lung Adenocarcinoma A549 Cells Mediated by Reduction in Claudin-2 and Nrf2 Expression.
UCHL3 promotes cervical cancer development and metastasis by stabilizing NRF2 via deubiquitination.
Evaluating the Anticancer Activity of Blocking TNF Type 1 Receptors in Thioacetamide-Induced Hepatocellular Carcinoma in a Rat Model.
Role of STAT3 and NRF2 in Tumors: Potential Targets for Antitumor Therapy.
Influence of Melatonin Treatment on Cellular Mechanisms of Redox Adaptation in K562 Erythroleukemic Cells.
Oxygen therapy accelerates apoptosis induced by selenium compounds via regulating Nrf2/MAPK signaling pathway in hepatocellular carcinoma.

J Biol Chem. 2022 Dec 14. pii: S0021-9258(22)01241-8. [Epub ahead of print] 102798

Nuclear factor Nrf2 promotes glycosidase OGG1 expression by activating the AKT pathway to enhance leukemia cell resistance to cytarabine.

Qin Shang, Chengyun Pan, Xi Zhang, Tonghua Yang, Tianzhen Hu, Lin Zheng, Shuyun Cao, Cheng Feng, Xiuying Hu, Xiao Chai, Jishi Wang, Qin Fang.

  Chemotherapy resistance is the dominant challenge in the treatment of acute myeloid leukemia (AML). Nuclear factor E2 related factor 2 (Nrf2) exerts a vital function in drug resistance of many tumors. Nevertheless, the potential molecular mechanism of Nrf2 regulating the base excision repair (BER) pathway that mediates AML chemotherapy resistance remains unclear. Here, in clinical samples, we found that the high expression of Nrf2 and BER pathway gene encoding 8-hydroxyguanine DNA glycosidase (OGG1) was associated with AML disease progression. In vitro, Nrf2 and OGG1 were highly expressed in drug-resistant leukemia cell. Up-regulation of Nrf2 in leukemia cell by lentivirus transfection could decrease the sensitivity of leukemia cell to cytarabine, while down-regulation of Nrf2 in drug-resistant cells could enhance leukemia cell chemosensitivity. Meanwhile, we found that Nrf2 could positively regulate OGG1 expression in leukemia cell. Our ChIP assay revealed that Nrf2 could bind to the promoter of OGG1. Furthermore, the use of OGG1 inhibitor TH5487 could partially reverse the inhibitory effect of up-regulated Nrf2 on leukemia cell apoptosis. In vivo, down-regulation of Nrf2 could increase the sensitivity of leukemia cell to cytarabine and decrease OGG1 expression. Mechanistically, Nrf2-OGG1 axis-mediated AML resistance might be achieved by activating the AKT signaling pathway to regulate downstream apoptotic proteins. Thus, this study reveals a novel mechanism of Nrf2 promoting drug resistance in leukemia, which may provide a potential therapeutic target for the treatment of drug-resistant/refractory leukemia.

Keywords:  8-hydroxyguanine DNA glycosidase; acute myeloid leukemia; cytarabine; nuclear factor E2 related factor 2; resistance

DOI:  https://doi.org/10.1016/j.jbc.2022.102798
Cell Death Dis. 2022 Dec 20. 13(12): 1060

Blockage of Nrf2 and autophagy by L-selenocystine induces selective death in Nrf2-addicted colorectal cancer cells through p62-Keap-1-Nrf2 axis.

Wei-Lun Hsu, Chieh-Min Wang, Chao-Ling Yao, Ssu-Ching Chen, Chung-Yi Nien, Yang-Ho Sun, Tsung-Yu Tseng, Yueh-Hsia Luo.

Persistent Nrf2 activation is typically noted in many cancers, including colorectal cancer (CRC), aiding cancer cells in overcoming growth stress and promoting cancer progression. Sustained Nrf2 activation, which is beneficial for cancer cells, is called "Nrf2 addiction"; it is closely associated with malignancy and poor prognosis in patients with cancer. However, Nrf2 inhibitors may have adverse effects on normal cells. Here, we found that the selenocompound L-selenocystine (SeC) is selectively cytotoxic in the Nrf2-addicted CRC cell line WiDr cells, but not in non-Nrf2-addicted mesenchymal stem cells (MSCs) and normal human colon cells. Another CRC cell line, C2BBe1, which harbored lower levels of Nrf2 and its downstream proteins were less sensitive to SeC, compared with the WiDr cells. We further demonstrated that SeC inhibited Nrf2 and autophagy activation in the CRC cells. Antioxidant GSH pretreatment partially rescued the CRC cells from SeC-induced cytotoxicity and Nrf2 and autophagy pathway inhibition. By contrast, SeC activated Nrf2 and autophagy pathway in non-Nrf2-addicted MSCs. Transfecting WiDr cells with Nrf2-targeting siRNA decreased persistent Nrf2 activation and alleviated SeC cytotoxicity. In KEAP1-knockdown C2BBe1 cells, Nrf2 pathway activation increased SeC sensitivity and cytotoxicity. In conclusion, SeC selectively attacks cancer cells with constitutively activated Nrf2 by reducing Nrf2 and autophagy pathway protein expression through the P62-Nrf2-antioxidant response element axis and eventually trigger cell death.

DOI: https://doi.org/10.1038/s41419-022-05512-2
Am J Physiol Cell Physiol. 2022 Dec 19.

Sulforaphane attenuates cancer cell-induced atrophy of C2C12 myotubes.

Wenlan Li, Jennifer Trieu, Ronnie Blazev, Benjamin L Parker, Kate T Murphy, Kristy Swiderski, Gordon S Lynch.

  Cancer cachexia is common in many cancers and the loss of skeletal muscle mass compromises the response to therapies and quality of life. A contributing mechanism is oxidative stress and compounds able to attenuate it may be protective. Sulforaphane (SFN), a natural antioxidant in cruciferous vegetables, activates nuclear factor erythroid 2-related factor 2 (Nrf2) signaling to decrease oxidative stress. Although SFN has potential as a cancer therapeutic, whether it can attenuate muscle wasting in the absence or presence of chemotherapy is unknown. In healthy C2C12 myotubes, SFN administration for 48 h induced hypertrophy through increased myoblast fusion via Nrf2 and ERK signaling. To determine whether SFN could attenuate wasting induced by cancer cells, myotubes were co-cultured with or without Colon-26 (C-26) cancer cells for 48 h and treated with 5-fluorouracil (5-FU, 5 µM) or vehicle (DMSO). SFN (10 µM) or DMSO was added for the final 24 h. Co-culture with cancer cells in the absence and presence of 5-FU, reduced myotube width by ~30% (P < 0.001) and ~20% (P < 0.01), respectively, which was attenuated by SFN (P < 0.05). Exposure to C-26 conditioned media reduced myotube width by 15% (P < 0.001), which was attenuated by SFN. Western immunoblotting and qRT-PCR confirmed activation of Nrf2 signaling and antioxidant genes. Co-administration of Nrf2 inhibitors (ML-385) or MEK inhibitors (PD184352) revealed SFN's attenuation of atrophy was blocked by ERK inhibition. These data support the chemoprotective and antioxidative function of SFN in myotubes, highlighting its therapeutic potential for cancer-related muscle wasting.

Keywords:  antioxidant; cancer cachexia; muscle wasting; skeletal muscle; sulforaphane

DOI:  https://doi.org/10.1152/ajpcell.00025.2022
Cancers (Basel). 2022 Dec 12. pii: 6120. [Epub ahead of print]14(24):

A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations.

Rayhaneh Afjei, Negar Sadeghipour, Sukumar Uday Kumar, Mallesh Pandrala, Vineet Kumar, Sanjay V Malhotra, Tarik F Massoud, Ramasamy Paulmurugan.

  TP53 tumor suppressor gene is a commonly mutated gene in cancer. p53 mediated senescence is critical in preventing oncogenesis in normal cells. Since p53 is a transcription factor, mutations in its DNA binding domain result in the functional loss of p53-mediated cellular pathways. Similarly, nuclear factor erythroid 2-related factor 2 (Nrf2) is another transcription factor that maintains cellular homeostasis by regulating redox and detoxification mechanisms. In glioblastoma (GBM), Nrf2-mediated antioxidant activity is upregulated while p53-mediated senescence is lost, both rendering GBM cells resistant to treatment. To address this, we identified novel Nrf2 inhibitors from bioactive compounds using a molecular imaging biosensor-based screening approach. We further evaluated the identified compounds for their in vitro and in vivo chemotherapy enhancement capabilities in GBM cells carrying different p53 mutations. We thus identified an Nrf2 inhibitor that is effective in GBM cells carrying the p53 (R175H) mutation, a frequent clinically observed hotspot structural mutation responsible for chemotherapeutic resistance in GBM. Combining this drug with low-dose chemotherapies can potentially reduce their toxicity and increase their efficacy by transiently suppressing Nrf2-mediated detoxification function in GBM cells carrying this important p53 missense mutation.

Keywords:  Nrf2; chemotherapy; glioblastoma; p53; small molecule compounds

DOI:  https://doi.org/10.3390/cancers14246120
Int J Mol Sci. 2022 Dec 07. pii: 15447. [Epub ahead of print]23(24):

Elevation of Anticancer Drug Toxicity by Caffeine in Spheroid Model of Human Lung Adenocarcinoma A549 Cells Mediated by Reduction in Claudin-2 and Nrf2 Expression.

Hiroaki Eguchi, Riho Kimura, Saki Onuma, Ayaka Ito, Yaqing Yu, Yuta Yoshino, Toshiyuki Matsunaga, Satoshi Endo, Akira Ikari.

  Claudin-2 (CLDN2), a component of tight junctions, is abnormally expressed in human lung adenocarcinoma tissue. CLDN2 contributes to chemoresistance in human lung adenocarcinoma-derived A549 cells, and it may be a target for cancer therapy. Here, we found that coffee ingredients, namely caffeine and theobromine, decreased the protein level of CLDN2 in human lung adenocarcinoma-derived A549 cells. In contrast, other components, such as theophylline and chlorogenic acid, had no effect. These results indicate that the 7-methyl group in methylxanthines may play a key role in the reduction in CLDN2 expression. The caffeine-induced reduction in the CLDN2 protein was inhibited by chloroquine, a lysosome inhibitor. In a protein-stability assay using cycloheximide, CLDN2 protein levels decreased faster in caffeine-treated cells than in vehicle-treated cells. These results suggest that caffeine accelerates the lysosomal degradation of CLDN2. The accumulation and cytotoxicity of doxorubicin were dose-dependently increased, which was exaggerated by caffeine but not by theophylline in spheroids. Caffeine decreased nuclear factor-erythroid 2-related factor 2 (Nrf2) levels without affecting hypoxia-inducible factor-1α levels. Furthermore, caffeine decreased the expression of Nrf2-targeted genes. The effects of caffeine on CLDN2 expression and anticancer-drug-induced toxicity were also observed in lung adenocarcinoma RERF-LC-MS cells. We suggest that caffeine enhances doxorubicin-induced toxicity in A549 spheroids mediated by the reduction in CLDN2 and Nrf2 expression.

Keywords:  caffeine; chemoresistance; claudin-2; lung adenocarcinoma

DOI:  https://doi.org/10.3390/ijms232415447
Biochem Biophys Res Commun. 2022 Nov 23. pii: S0006-291X(22)01620-5. [Epub ahead of print]641 132-138

UCHL3 promotes cervical cancer development and metastasis by stabilizing NRF2 via deubiquitination.

Yuan Zhang, Jing-Bo Liu, Jing Liu, Mengjun Liu, Hong-Li Liu, Jing Zhang.

  Cervical cancer is one of the most lethal gynaecological malignancies in females. The deubiquitylase UCHL3 has been studied as an oncogenic factor in multiple cancers. However, the expression pattern and function profile of UCHL3 in cervical cancer hasn't been fully characterized. Here, we revealed that UCHL3 was highly expressed in cervical cancer and overexpressed UCHL3 predicted a poor survival probability in cervical cancer patients. Our findings showed that knockdown of UCHL3 inhibited cell growth, migration and invasion in cervical cancer cells while UCHL3 knockdown inhibited cervical cancer development and metastasis in vivo in mouse models. Mechanistically, co-immunoprecipitation assay showed that UCHL3 directly interacted with NRF2. Knockdown of UCHL3 decreased NRF2 expression while overexpression of UCHL3 stabilized NRF2 via deubiquitination. In addition, overexpression of UCHL3 with C92A mutation didn't affect NRF2 stability. Moreover, we revealed that overexpression of NRF2 could antagonize the function of UCHL3 knockdown in cervical cancer cells. Collectively, our findings suggest that UCHL3 promotes cervical cancer development and metastasis by stabilizing NRF2 via deubiquitination. Thus, UCHL3/NRF2 axis could be utilized to develop efficient treatments for cervical cancer patients.

Keywords:  Cervical cancer; Metastasis; NRF2; UCHL3; Ubiquitination

DOI:  https://doi.org/10.1016/j.bbrc.2022.11.065
Cureus. 2022 Dec;14(12): e32519

Evaluating the Anticancer Activity of Blocking TNF Type 1 Receptors in Thioacetamide-Induced Hepatocellular Carcinoma in a Rat Model.

Alaa Bagalagel, Reem Diri, Ahmed Noor, Deina Almasri, Hussain Bakhsh, Hussam I Kutbi, Mohammed M Al-Gayyar.

  Background Hepatocellular carcinoma (HCC) can explicate about 90% of the total primary liver cancer cases, with approximately 800,000 new cases identified each year worldwide. In addition, any changes in the expression of the tumor necrosis factor α (TNF-α) type 1 receptor (TNFR1) might impact many biological processes, which may lead to cancer. Aims We conducted the following study to investigate the ability of CAY10500, a TNF-α inhibitor that prevents binding to the TNF receptor 1, to produce anticancer effects against hepatocellular carcinoma experimentally induced in rats and to discover its effect on nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Materials and methods HCC was induced in rats via 200 mg/kg thioacetamide followed by treating some rats with IV 1 mg/kg CAY10500. Assessment of the liver impairment was by measuring the serum α-fetoprotein (AFP) and investigation of liver sections stained with hematoxylin/eosin. The hepatic expression of both the messenger RNA (mRNA) and protein levels of TNF-α, TNFR1, Nrf2, and HO-1 was assessed. Results We found that CAY10500 increased the survival percent of rats associated with a reduction in serum AFP and the number of hepatic nodules. Besides, CAY10500 reduced the expression of TNFR1 without affecting the expression of TNF-α. Finally, CAY10500 increased the expression of both Nrf2 and HO-1. Conclusions Inhibition of TNFR1 expression in HCC by using CAY10500 produced therapeutic effects as indicated by increasing the survival rate, reducing the serum AFP level, decreasing liver nodules, and improving hepatocytes' structure. In addition, TNFR1 significantly enhanced the expression of Nrf2 and HO-1.

Keywords:  heme oxygenase-1 (ho-1); hepatocellular carcinoma (hcc); nuclear factor erythroid 2-related factor 2 (nrf2); tnf-α type 1 receptor (tnfr1); tumor necrosis factor (tnf)-α

DOI:  https://doi.org/10.7759/cureus.32519
Molecules. 2022 Dec 10. pii: 8768. [Epub ahead of print]27(24):

Role of STAT3 and NRF2 in Tumors: Potential Targets for Antitumor Therapy.

Yanjun Tian, Haiqing Liu, Mengwei Wang, Ruihao Wang, Guandong Yi, Meng Zhang, Ruijiao Chen.

  Signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid-derived 2-like 2 (NRF2, also known as NFE2L2), are two of the most complicated transcription regulators, which participate in a variety of physiological processes. Numerous studies have shown that they are overactivated in multiple types of tumors. Interestingly, STAT3 and NRF2 can also interact with each other to regulate tumor progression. Hence, these two important transcription factors are considered key targets for developing a new class of antitumor drugs. This review summarizes the pivotal roles of the two transcription regulators and their interactions in the tumor microenvironment to identify potential antitumor drug targets and, ultimately, improve patients' health and survival.

Keywords:  NRF2; STAT3; antitumor therapy; signal transduction; tumor

DOI:  https://doi.org/10.3390/molecules27248768
Genes (Basel). 2022 Dec 11. pii: 2337. [Epub ahead of print]13(12):

Influence of Melatonin Treatment on Cellular Mechanisms of Redox Adaptation in K562 Erythroleukemic Cells.

Flaviene Felix Torres, Victoria Simões Bernardo, Carla Peres de Paula, João Pedro Maia de Oliveira da Silva, Eduardo Alves de Almeida, Anderson Ferreira da Cunha, Danilo Grünig Humberto da Silva.

  Melatonin (MEL) presents well-documented pleiotropic actions against oxidative stress (OS), acting indirectly through activation of transcription factors, e.g., FoxO3 and Nrf2. Thus, this study aimed to investigate the possible modulating effects of MEL on the redox signaling pathways PI3K/AKT/FoxO3 and Keap1/Nrf2/ARE in K562 erythroleukemic cells subjected to OS induction. For this, the viability, and transcript levels of genes involved in redox adaptation were evaluated in K562 cells in different periods of erythroid differentiation: under OS induction by hydrogen peroxide (100 µM H2O2); treated with 1 nM (C1) and 1 mM (C2) MEL; and associated or not with stress induction. We observed a restoration of physiological levels of Nrf2 in both MEL concentrations under OS. The C1 was related to enhanced expression of antioxidant and proteasome genes through the Nrf2-ARE pathway, while C2 to the induction of FOXO3 expression, suggesting an involvement with apoptotic pathway, according to BIM transcript levels. The effects of MEL administration in these cells showed a period and dose-dependent pattern against induced-OS, with direct and indirect actions through different pathways of cellular adaptation, reinforcing the importance of this indolamine in the regulation of cellular homeostasis, being a promising therapeutic alternative for diseases that present an exacerbated OS.

Keywords:  FoxO3; N-[2-(5-methoxy-1H-indol-3-yl)ethyl]; Nrf2; antioxidant therapy

DOI:  https://doi.org/10.3390/genes13122337
Pharmacol Res. 2022 Dec 20. pii: S1043-6618(22)00570-9. [Epub ahead of print] 106624

Oxygen therapy accelerates apoptosis induced by selenium compounds via regulating Nrf2/MAPK signaling pathway in hepatocellular carcinoma.

Cheng Wang, Tingting Cheng, Qianqian Lu, Wenzhen Li, Ben Liu, Lijun Yue, Maoru Du, Wenxue Sheng, Zhaochen Lu, Jingnan Yang, Feng Geng, Xue Gao, Junhong Lü, Xiaohong Pan.

  Selenium has good antitumor effects in vitro, but the hypoxic microenvironment in solid tumors makes its clinical efficacy unsatisfactory. We hypothesized that the combination with oxygen therapy might improve the treatment efficacy of selenium in hypoxic tumors through the changes of redox environment. In this work, two selenium compounds, Na2SeO3 and CysSeSeCys, were selected to interrogate their therapeutic effects on hepatocellular carcinoma (HCC) under different oxygen levels. In tumor-bearing mice, both selenium compounds significantly inhibited the tumor growth, and combined with oxygen therapy further reduced the tumor volume about 50%. In vitro HepG2 cell experiments, selenium induced autophagy and delayed apoptosis under hypoxia (1% O2), while inhibited autophagy and accelerated apoptosis under hyperoxia (60% O2). We found that, in contrast to hypoxia, the hyperoxic environment facilitated the H2Se, produced by the selenium metabolism in cells, to be rapidly oxidized to generate H2O2, leading to inhibit the expression level of Nrf2 and to increase that of phosphorylation of p38 and MKK4, resulting in inhibiting autophagy and accelerating apoptosis. Once the Nrf2 gene was knocked down, selenium compounds combined with hyperoxia treatment would further activate the MAPK signaling pathway and further increase apoptosis. These findings highlight oxygen can significantly enhance the anti-HCC effect of selenium compounds through regulating the Nrf2 and MAPK signaling pathways, thus providing novel therapeutic strategy for the hypoxic tumors and pave the way for the application of selenium in clinical treatment.

Keywords:  MAPK; Nrf2; hepatocellular carcinoma; oxygen therapy; selenium compounds

DOI:  https://doi.org/10.1016/j.phrs.2022.106624