bims-nurfca 2024-02-04 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024‒02‒04
eleven papers selected by
Caner Geyik, Istinye University

Acyltransferase zinc finger DHHC-type containing 2 aggravates gastric carcinoma growth by targeting Nrf2 signaling: A mechanism-based multicombination bionic nano-drug therapy.
Overexpression of Nrf2 reverses ferroptosis induced by Arenobufagin in gastric cancer.
A NRF2 Regulated and the Immunosuppressive Microenvironment Reversed Nanoplatform for Cholangiocarcinoma Photodynamic-Gas Therapy.
Proapoptotic effect of WS-299 induced by NOXA accumulation and NRF2-counterbalanced oxidative stress damage through targeting RBX1-UBE2M interaction in gastric cancers.
Radiotherapy induces an increase in serum antioxidant capacity reflecting tumor response.
Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.
Ferulic acid interventions ameliorate NDEA-CCl4-induced hepatocellular carcinoma via Nrf2 and p53 upregulation and Akt/PKB-NF-κB-TNF-α pathway downregulation in male Wistar rats.
Edaravone and obeticholic acid protect against cisplatin-induced heart toxicity by suppressing oxidative stress and inflammation and modulating Nrf2, TLR4/p38MAPK, and JAK1/STAT3/NF-κB signals.
CPT1B maintains redox homeostasis and inhibits ferroptosis to induce gemcitabine resistance via the KEAP1/NRF2 axis in pancreatic cancer.
Apigenin promotes apoptosis of 4T1 cells through PI3K/AKT/Nrf2 pathway and improves tumor immune microenvironment in vivo.
PM2.5-induced DNA oxidative stress in A549 cells and regulating mechanisms by GST DNA methylation and Keap1/Nrf2 pathway.

Redox Biol. 2024 Jan 23. pii: S2213-2317(24)00027-2. [Epub ahead of print]70 103051

Acyltransferase zinc finger DHHC-type containing 2 aggravates gastric carcinoma growth by targeting Nrf2 signaling: A mechanism-based multicombination bionic nano-drug therapy.

Luguang Liu, Longgang Wang, Liqing Liu, Xianlin Qu, Weizhu Zhao, Jishuang Ding, Siwei Zhao, Botao Xu, Hang Yu, Bing Liu, Jie Chai.

  The significant regulatory role of palmitoylation modification in cancer-related targets has been demonstrated previously. However, the biological functions of Nrf2 in stomach cancer and whether the presence of Nrf2 palmitoylation affects gastric cancer (GC) progression and its treatment have not been reported. Several public datasets were used to look into the possible link between the amount of palmitoylated Nrf2 and the progression and its outcome of GC in patients. The palmitoylated Nrf2 levels in tumoral and peritumoral tissues from GC patients were also evaluated. Both loss-of-function and gain-of-function via transgenic experiments were performed to study the effects of palmitoylated Nrf2 on carcinogenesis and the pharmacological function of 2-bromopalmitate (2-BP) on the suppression of GC progression in vitro and in vitro. We discovered that Nrf2 was palmitoylated in the cytoplasmic domain, and this lipid posttranslational modification causes Nrf2 stabilization by inhibiting ubiquitination, delaying Nrf2 destruction via the proteasome and boosting nuclear translocation. Importantly, we also identify palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 2 (DHHC2) as the primary acetyltransferase required for the palmitoylated Nrf2 and indicate that the suppression of Nrf2 palmitoylation via 2-bromopalmitate (2-BP), or the knockdown of DHHC2, promotes anti-cancer immunity in vitro and in mice model-bearing xenografts. Of note, based on the antineoplastic mechanism of 2-BP, a novel anti-tumor drug delivery system ground 2-BP and oxaliplatin (OXA) dual-loading gold nanorods (GNRs) with tumor cell membrane coating biomimetic nanoparticles (CM@GNRs-BO) was established. In situ photothermal therapy is done using near-infrared (NIR) laser irradiation to help release high-temperature-triggered drugs from the CM@GNRs-BO reservoir when needed. This is done to achieve photothermal/chemical synergistic therapy. Our findings show the influence and linkage of palmitoylated Nrf2 with tumoral and peritumoral tissues in GC patients, the underlying mechanism of palmitoylated Nrf2 in GC progression, and novel possible techniques for addressing Nrf2-associated immune evasion in cancer growth. Furthermore, the bionic nanomedicine developed by us has the characteristics of dual drugs delivery, homologous tumor targeting, and photothermal and chemical synergistic therapy, and is expected to become a potential platform for cancer treatment.

Keywords:  2-Bromopalmitate; DHHC2; Dual-drug loading gold nanorods (GNRs) system; Palmitoylation; Stomach cancer

DOI:  https://doi.org/10.1016/j.redox.2024.103051
Toxicol Appl Pharmacol. 2024 Jan 31. pii: S0041-008X(24)00040-1. [Epub ahead of print] 116842

Overexpression of Nrf2 reverses ferroptosis induced by Arenobufagin in gastric cancer.

Jiao Long, Wenjun Wang, Jing Chu, Yueyue Li, Meng Wang, Jingjing Su, Yuting Yang, GuoKai Wang, Qinglin Li, Hui Cheng.

  Arenobufagin (ArBu) is a natural monomer extracted and isolated from the secretion of the Chinese toad, also known as toad venom. This compound exerts anti-tumor effects by promoting apoptosis in tumor cells, inhibiting tumor angiogenesis, and preventing the invasion and migration of tumor cells. However, their impact on ferroptosis in tumor cells has yet to be fully confirmed. In this study, we established a subcutaneous transplant tumor model in nude mice to investigate the inhibitory effect of ArBu on gastric cancer cells (MGC-803) and the safety of drug delivery. in vitro experiments, we screened the most sensitive cancer cell lines using the MTT method and determined the response of ArBu to cell death. Use flow cytometry to measure cytoplasmic and lipid reactive oxygen species (ROS) levels. Determine the expression levels of ferritin-related proteins through Western blot experiments. In addition, a MGC-803 cell model overexpressing Nrf2 was created using lentiviral transfection to investigate the role of ArBu in inducing ferroptosis in cancer cells. Our research findings indicate that ArBu inhibits the proliferation of MGC-803 cells and is linked to ferroptosis. In summary, our research findings indicate that ArBu is a potential anti-gastric cancer drug that can induce ferroptosis in human cancer cells through the Nrf2/SLC7A11/GPX4 pathway.

Keywords:  Arenobufagin; Ferroptosis; Gastric cancer; Nrf2/SLC7A11/GPX4 pathway

DOI:  https://doi.org/10.1016/j.taap.2024.116842
Adv Sci (Weinh). 2024 Feb 02. e2307143

A NRF2 Regulated and the Immunosuppressive Microenvironment Reversed Nanoplatform for Cholangiocarcinoma Photodynamic-Gas Therapy.

Weimin Wang, Yang Gao, Jianjun Xu, Tianhao Zou, Bin Yang, Shaobo Hu, Xiang Cheng, Yun Xia, Qichang Zheng.

  Photodynamic therapy (PDT) is a minimally invasive and controllable local cancer treatment for cholangiocarcinoma (CCA). However, the efficacy of PDT is hindered by intratumoral hypoxia and the presence of an antioxidant microenvironment. To address these limitations, combining PDT with gas therapy may be a promising strategy to enhance tumor oxygenation. Moreover, the augmentation of oxidative damage induced by PDT and gas therapy can be achieved by inhibiting NRF2, a core regulatory molecule involved in the antioxidant response. In this study, an integrated nanotherapeutic platform called CMArg@Lip, incorporating PDT and gas therapies using ROS-responsive liposomes encapsulating the photosensitizer Ce6, the NO gas-generating agent L-arginine, and the NRF2 inhibitor ML385, is successfully developed. The utilization of CMArg@Lip effectively deals with challenges posed by tumor hypoxia and antioxidant microenvironment, resulting in elevated levels of oxidative damage and subsequent induction of ferroptosis in CCA. Additionally, these findings suggest that CMArg@Lip exhibits notable immunomodulatory effects, including the promotion of immunogenic cell death and facilitation of dendritic cell maturation. Furthermore, it contributes to the anti-tumor function of cytotoxic T lymphocytes through the downregulation of PD-L1 expression in tumor cells and the activation of the STING signaling pathway in myeloid-derived suppressor cells, thereby reprogramming the immunosuppressive microenvironment via various mechanisms.

Keywords:  NRF2; ferroptosis; gas therapy; photodynamic therapy; tumor microenvironment reversal

DOI:  https://doi.org/10.1002/advs.202307143
Bioorg Chem. 2024 Jan 23. pii: S0045-2068(24)00047-6. [Epub ahead of print]144 107142

Proapoptotic effect of WS-299 induced by NOXA accumulation and NRF2-counterbalanced oxidative stress damage through targeting RBX1-UBE2M interaction in gastric cancers.

Ting Ma, Qianqian Song, Bing Cheng, Enhui Guo, Xiaoru Wang, Meng Li, Mengge Dai, Shaotong Li, Siqi Feng, Bin Yu.

  The abnormal activation of Cullin RING E3 Ligases (CRLs) is closely associated with the occurrence and development of various cancers. Targeting the neddylation pathway represents an effective approach for cancer treatment. In this work, we reported that WS-299, structurally featuring a coumarin moiety attached to the triazolopyrimidine, exhibited excellent anti-proliferative activity in MGC-803 and HGC-27 cells. WS-299 exerted potent anticancer effects by inhibiting clone formation, EdU incorporation and inducing cell cycle arrest. WS-299 inhibited CUL3/5 neddylation and caused an obvious accumulation of Nrf2 and NOXA, substrates of CRL3 and CRL5, respectively. Biochemical studies showed that WS-299 inhibited CUL3 neddylation by inhibiting RBX1-UBE2M interaction. The anti-proliferative effect of WS-299 was mainly induced by NOXA-mediated apoptosis. Of note, Nrf2 attenuated WS-299-induced reactive oxygen species (ROS) levels. Furthermore, Nrf2 accumulation also had an antagonistic effect on NOXA-induced apoptosis. Therefore, WS-299 and siNrf2 synergistically increased ROS levels, apoptotic cells and suppressed tumor growth in vivo. Taken together, our research clarified the anti-cancer mechanisms of WS-299 through targeting the RBX1-UBE2M protein-protein interaction and inhibiting the neddylation modification of CUL3 and CUL5. More importantly, our studies also demonstrated that combination of WS-299 with shNrf2 could be an effective strategy for treating gastric cancers.

Keywords:  Cullin neddylation; Gastric cancers; NOXA accumulation; Nrf2; RBX1-UBE2M interaction

DOI:  https://doi.org/10.1016/j.bioorg.2024.107142
Clin Transl Radiat Oncol. 2024 Mar;45 100726

Radiotherapy induces an increase in serum antioxidant capacity reflecting tumor response.

F V Naumann, J H A M Kaanders, W J M Peeters, G J Adema, F C G J Sweep, J Bussink, P N Span.

  Background and purpose: Radiotherapy (RT) is a mainstay component of treatment for patients with head and neck squamous cell carcinoma (HNSCC), but responses vary. As RT relies upon oxidative damage, antioxidant expression in response to RT-induced reactive oxygen species (ROS) could compromise treatment response. We aimed to examine local and systemic antioxidant responses to increased RT-induced ROS in relation to treatment success.Materials and methods: Nuclear factor erythroid 2-related factor 2 (NRF2), the main antioxidant transcription factor, was immunofluorescently stained in FaDu cells and in tumor biopsies of patients with oral cavity/oropharynx HNSCC before and after five fractions of RT. Besides, total antioxidant capacity (TAC) was analyzed in HNSCC tumor cells in vitro and in serum of HNSCC patients before, during, and after RT.
Results: Data revealed an increase in NRF2 expression and TAC in head and neck cancer cells in vitro over the course of 5 daily fractions of 2 Gy. In accordance, also in patients' tumors NRF2 expression increased, which was associated with increased serum TAC during RT. Increasing serum TAC was related to impaired local tumor control.
Conclusion: Radiation induced NRF2 expression and upregulated TAC, which may compromise the effect of RT-induced ROS. Changes in serum TAC during RT could serve as a novel predictor of treatment outcome in HNSCC patients.Medical Ethics Review Committee (CMO) approval - CMO number: 2007/104.

Keywords:  Antioxidants; Head and neck cancers; NF-E2-related factor 2 (NRF2); Oropharynx; Oxidative stress; Reactive oxygen species; Squamous cell carcinoma of head and neck

DOI:  https://doi.org/10.1016/j.ctro.2024.100726
bioRxiv. 2024 Jan 19. pii: 2024.01.16.575895. [Epub ahead of print]

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jacek Biesiada, Katherine E Vest, Pier P Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, J Tom Cunningham, Maria F Czyzyk-Krzeska.

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H 2 O 2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC. Accumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth.Cu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis.Cu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes. Cu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of Cu Hi cells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H 2 O 2 Fenton-like reaction mediated cell death. Progression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth.

DOI: https://doi.org/10.1101/2024.01.16.575895
Toxicol Rep. 2024 Jun;12 119-127

Ferulic acid interventions ameliorate NDEA-CCl4-induced hepatocellular carcinoma via Nrf2 and p53 upregulation and Akt/PKB-NF-κB-TNF-α pathway downregulation in male Wistar rats.

Oluwatobi T Somade, Babajide O Ajayi, Olubisi E Adeyi, Temitope A Dada, Mukodaz A Ayofe, David C Inalu, Opeyemi I Ajiboye, Olaoluwawunmi M Shonoiki, Aminat O Adelabu, Rasaq T Onikola, Ismaila D Isiaka, Opeyemi Omotoso, Adewale S James, Tunde O Olaniyan, Ayodeji M Adegoke, Adio J Akamo, Babatunji E Oyinloye, Ezekiel Adewole.

  Hepatocellular carcinoma is a prevalent form of liver cancer that is life threatening. Many chemically synthesized anti-cancer drugs have various degrees of side effects. Hence, this study investigated the effect of FEAC interventions on NDEA-CCl4-induced HCAR in male Wistar rats. HCAR was induced by intraperitoneal administration of 200 mg/kg of NDEA and 0.5 mL/kg CCl4 (as a promoter of HCAR). Following the induction of HCAR, rats were treated differently with two different doses (25 and 50 mg/kg) of FEAC. HCAR induction was confirmed by the significant elevation of serum levels of ALT, AST, and α-FP. Also elevated significantly were liver levels of Akt/PKB, NF-κB, TNF-α, MDA, GSH, and activities of GST, SOD, and CAT, while levels of liver p53 and Nrf2 were significantly lowered compared with normal rats. Treatment interventions with both 25 and 50 mg/kg of FEAC against the DEN-CCl4-induced HCAR gave comparable effects, marked by a significant reduction in the levels of serum ALT, AST and α-FP, as well as liver levels of MDA, GSH, Akt/PKB, NF-κB, TNF-α, GST, SOD, and CAT, while levels of liver p53 and Nrf2 were significantly elevated compared with normal rats. Put together and judging by the outcomes of this study, FEAC being a potent antioxidant may also be potent against chemical-induced HCAR via upregulation of p53 and Nrf2, as well as downregulation of the Akt/PKB-NF-κB pathway in rats.

Keywords:  Akt; DEN; Ferulic acid; Hepatocellular carcinoma; NF-κB; Nrf2; P53; α-FP

DOI:  https://doi.org/10.1016/j.toxrep.2024.01.006
Naunyn Schmiedebergs Arch Pharmacol. 2024 Jan 29.

Edaravone and obeticholic acid protect against cisplatin-induced heart toxicity by suppressing oxidative stress and inflammation and modulating Nrf2, TLR4/p38MAPK, and JAK1/STAT3/NF-κB signals.

Ehab A M El-Shoura, Emad H M Hassanein, Hesham H Taha, Abdel-Gawad S Shalkami, Mohamed Mahmoud Hussein Hassanein, Fares E M Ali, Adel G Bakr.

  Cardiotoxicity is a significant adverse effect of cisplatin (CIS) that necessitates extensive medical care. The current study examines the cardioprotective effects of edaravone (EDV), obeticholic acid (OCA), and their combinations on CIS-induced cardiac damage. Rats were allocated into five groups: the normal control group, the remaining four groups received CIS (7.5 mg/kg, i.p.) as a single dose on the fifth day and were assigned to CIS, OCA (10 mg/kg/day) + CIS, EDV (20 mg/kg/day) + CIS, and the (EDV + OCA) + CIS group. Compared to the CIS-treated group, co-treating rats with EDV, OCA, or their combinations significantly decreased ALP, AST, LDH, CK-MB, and troponin-I serum levels and alleviated histopathological heart abnormalities. Biochemically, EDV, OCA, and EDV plus OCA administration mitigated cardiac oxidative stress as indicated by a marked decrease in heart MDA content with a rise in cardiac antioxidants SOD and GSH associated with upregulating Nrf2, PPARγ, and SIRT1 expression. Besides, it dampened inflammation by decreasing cardiac levels of TNF-α, IL-1β, and IL-6, mediated by suppressing NF-κB, JAK1/STAT3, and TLR4/p38MAPK signal activation. Notably, rats co-administered with EDV plus OCA showed noticeable protection that exceeded that of EDV and OCA alone. In conclusion, our study provided that EDV, OCA, and their combinations effectively attenuated CIS-induced cardiac intoxication by activating Nrf2, PPARγ, and SIRT1 signals and downregulating NF-κB, JAK1/STAT3, and TLR4/p38MAPK signals.

Keywords:  Cardiotoxicity; Cisplatin; Edaravone; Nrf2, JAK1/STAT3/NF-κB; Obeticholic acid

DOI:  https://doi.org/10.1007/s00210-024-02956-5
Surgery. 2024 Jan 31. pii: S0039-6060(23)00963-7. [Epub ahead of print]

CPT1B maintains redox homeostasis and inhibits ferroptosis to induce gemcitabine resistance via the KEAP1/NRF2 axis in pancreatic cancer.

Abudureyimu Tuerhong, Jin Xu, Wei Wang, Si Shi, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Xianjun Yu, Chen Liang.

BACKGROUND: Although we have made progress in treatment and have increased the 5-year survival by ≤30% in pancreatic cancer, chemotherapy resistance remains a major obstacle. However, whether reprogrammed lipid metabolism contributes to chemoresistance still needs to be further studied.METHODS: Gene expression was determined using Western blotting and quantitative reverse transcription polymerase chain reaction. Cell cloning formation assay, Cell Counting Kit-8, EdU assay, wound healing assay, transwell assay, and flow cytometry were used to detect apoptosis, cell proliferation capacity, migration capacity, and cytotoxicity of gemcitabine. Confocal fluorescence microscopy, transmission electron microscopy, etc., were used to detect the changes in intracellular reactive oxygen species, glutathione, lipid peroxidation level, and cell morphology. An animal study was performed to evaluate the effect of CPT1B knockdown on tumor growth and gemcitabine efficacy.
RESULTS: In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of pancreatic cancer cells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT1B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma.
CONCLUSION: CPT1B may act as a promising target in treating patients with gemcitabine-resistant pancreatic ductal adenocarcinoma .

DOI: https://doi.org/10.1016/j.surg.2023.12.019
Toxicol Res (Camb). 2024 Feb;13(1): tfae011

Apigenin promotes apoptosis of 4T1 cells through PI3K/AKT/Nrf2 pathway and improves tumor immune microenvironment in vivo.

Chu Zhang, Yupei Liao, Tangjia Li, Haijing Zhong, Luchen Shan, Pei Yu, Chenglai Xia, Lipeng Xu.

  The 2022 US Cancer Statistics show that breast cancer is one of the most common cancers in women. Epidemiology has shown that adding flavonoids to the diet inhibits cancers that arise in particular women, such as cervical cancer, ovarian cancer, and breast cancer. Although there have been research reports on apigenin (API) and breast cancer, its anti-tumor effect and potential mechanism on breast cancer have not yet been clarified. Therefore, in this study, we used 4T1 cells and a 4T1 xenograft tumor mouse model to investigate the antitumor effect of API on breast cancer and its underlying mechanism. In vitro, we used MTT, transwell, staining, and western blotting to investigate the inhibitory effect of apigenin on 4T1 and the underlying molecular mechanism. In vivo by establishing a xenograft tumor model, using immunohistochemistry, and flow cytometry to study the inhibitory effect of apigenin on solid breast tumors and its effect on the tumor immune microenvironment. The results showed that API can induce breast cancer cell apoptosis through the PI3K/AKT/Nrf2 pathway and can improve the tumor immune microenvironment in mice with breast tumors, thereby inhibiting the growth of breast cancer. Thus, API may be a promising agent for breast cancer treatment.

Keywords:  API; PI3K/AKT/Nrf2; Treg; apoptosis; breast cancer

DOI:  https://doi.org/10.1093/toxres/tfae011
Toxicol Mech Methods. 2024 Jan 31. 1-10

PM2.5-induced DNA oxidative stress in A549 cells and regulating mechanisms by GST DNA methylation and Keap1/Nrf2 pathway.

Ruijin Li, Chao Zhao, Yuexia Zhang, Wei Huang, Jiayi Wang, Guodong Cao, Zongwei Cai.

  Fine particulate matter (PM2.5) increases the risks of lung cancer. Epigenetics provides a new toxicology mechanism for the adverse health effects of PM2.5. However, the regulating mechanisms of PM2.5 exposure on candidate gene DNA methylation changes in the development of lung cancer remain unclear. Abnormal expression of the glutathione S transferase (GST) gene is associated with cancer. However, the relationship between PM2.5 and DNA methylation-mediated GST gene expression is not well understood. In this study, we performed GST DNA methylation analysis and GST-related gene expression in human A549 cells exposed to PM2.5 (0, 50, 100 µg/mL, from Taiyuan, China) for 24 h (n = 4). We found that PM2.5 may cause DNA oxidative damage to cells and the elevation of GSTP1 promotes cell resistance to reactive oxygen species (ROS). The Kelch-1ike ECH-associated protein l (Keap1)/nuclear factor NF-E2-related factor 2 (Nrf2) pathway activates the GSTP1. The decrease in the DNA methylation level of the GSTP1 gene enhances GSTP1 expression. GST DNA methylation is associated with reduced levels of 5-methylcytosine (5mC), DNA methyltransferase 1 (DNMT1), and histone deacetylases 3 (HDAC3). The GSTM1 was not sensitive to PM2.5 stimulation. Our findings suggest that PM2.5 activates GSTP1 to defend PM2.5-induced ROS and 8-hydroxy-deoxyguanosine (8-OHdG) formation through the Keap1/Nrf2 signaling pathway and GSTP1 DNA methylation.

Keywords:  A549 cell; DNA oxidative damage; Fine particulate matter; GST DNA methylation; Keap1/Nrf2 pathway

DOI:  https://doi.org/10.1080/15376516.2024.2307967