bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023‒12‒03
six papers selected by
Caner Geyik, Istinye University
  1. Oxidative Stress-regulating Enzymes and Endometrial Cancer Survival in Relation to Metformin Intake in Diabetic Patients.
  2. Erastin induces ferroptosis in cervical cancer cells via Nrf2/HO-1 signaling pathway.
  3. MiR-124-3p mediates gastric cancer cell ferroptosis induced by an anti-cancer drug polyphyllin I.
  4. Potentially Functional Genetic Variants in the NRF2 Signaling Pathway Genes are Associated With HBV-related Hepatocellular Carcinoma Survival.
  5. Regulation of antioxidants in cancer.
  6. Umbelliferone attenuates cisplatin-induced acute kidney injury by inhibiting oxidative stress and inflammation via NRF2.
  1. Anticancer Res. 2023 Dec;43(12): 5545-5554
    Oxidative Stress-regulating Enzymes and Endometrial Cancer Survival in Relation to Metformin Intake in Diabetic Patients.
    Ewelina Kuusiniemi, Peeter Karihtala, Ulla Puistola, Anne Ahtikoski, Elina Urpilainen.
      BACKGROUND/AIM: Metformin inhibits tumorigenesis in endometrial carcinoma and interferes with the expression of oxidative stress-regulating proteins, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1). Although manganese superoxide dismutase (MnSOD) is vital for withstanding mitochondrial oxidative stress, it has also been linked with chemoresistance and poorer outcomes in several cancer types. However, data on endometrial cancers are limited. This study aimed to highlight the relationship between mitochondrial redox regulation and endometrial cancer survival in relation to metformin consumption in women with type 2 diabetes mellitus (T2DM).PATIENTS AND METHODS: Our retrospective hospital-based cohort study included 121 patients diagnosed with endometrial carcinoma and T2DM between 2007 and 2014. Fifty-eight patients were using metformin at the time of diagnosis. Nrf2 and Keap1 expression levels in the tumor samples were assessed immunohistochemically, and MnSOD levels were measured both immunohistochemically and from the serum samples.
    RESULTS: High MnSOD tissue expression was associated with better overall survival among metformin users in the univariate analysis (p=0.03). When adjusted for histology and stage, high serum MnSOD was associated with better overall survival (HR=0.22, 95%CI=0.07-0.71, p=0.01). No association was found between MnSOD, Nrf2, or Keap1 and overall survival among metformin non-users.
    CONCLUSION: Higher expression of MnSOD in patients with endometrial cancer and T2DM is associated with better overall survival if the patient is consuming metformin.
    Keywords:  Endometrial carcinoma; Keap1; MnSOD; Nrf2; metformin; oxidative stress; type 2 diabetes
    DOI:  https://doi.org/10.21873/anticanres.16756
  2. Int J Immunopathol Pharmacol. 2023 Jan-Dec;37:37 3946320231219348
    Erastin induces ferroptosis in cervical cancer cells via Nrf2/HO-1 signaling pathway.
    Xiaoning Wei, Qiaoqiao Huang, Jinbing Huang, Li Yu, Junying Chen.
      OBJECTIVE: Our research aims to assess the influence of erastin, a ferroptosis-inducing agent, on cervical cancer cells.INTRODUCTION: Cervical cancer is a prevalent malignancy in females. Dysregulation of ferroptosis, a form of cell demise reliant on iron, is implicated in several cancers.
    METHODS: The effect of erastin on HeLa and SiHa was detected by transwell assay, scratch test, and colony formation assay, while cell apoptosis was detected using flow cytometry. Cellular reactive oxygen species (ROS) generation was detected using the dichloro-dihydro-fluorescein diacetate assay. Sequencing analysis identified differentially expressed genes (DEGs), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment analyses were employed to identify the target gene. Subsequently, the utilization of small interfering RNA (siRNA) was employed to suppress the targeted gene expression in HeLa cells, thereby effectively mitigating the impact of erastin on various cellular processes including invasion, colony formation, migration, and ROS generation.
    RESULTS: The findings indicate that erastin attenuates the viability of both HeLa cells (IC50 = 30.88 µM) and SiHa cells (IC50 = 29.40 µM). Treatment with erastin at 10 µM inhibits the invasion, colony formation, and migration of both HeLa and SiHa cells within 24 h. Ferrostatin-1 (1 µM) notably alleviates the inhibitory effects of erastin of HeLa and SiHa cells. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target, heme oxygenase-1 (HO-1), was found in erastin-treated cells compared to the control group. When knocked down HO-1 in HeLa cells, effectively counteracting the effects of erastin on the invasion, colony formation, migration, and ROS production in HeLa cells.
    CONCLUSION: Our research demonstrates that erastin induces ferroptosis and the accumulation of ROS in cervical cancer cells by activating the Nrf2/HO-1 pathway, significantly reducing cell proliferation and motility. These findings propose a potential molecular mechanism of erastin-mediated cervical cancer development.
    Keywords:  Nrf2; cervical cancer; erastin; ferroptosis; heme oxygenase-1; reactive oxygen species
    DOI:  https://doi.org/10.1177/03946320231219348
  3. Front Pharmacol. 2023 ;14 1285799
    MiR-124-3p mediates gastric cancer cell ferroptosis induced by an anti-cancer drug polyphyllin I.
    Fang Zheng, Jian-Can Bi, Yu-Yan Wei, Yeshu Wang, Qunfang Zhang, Chun-Ling Liang, Jianwei Wu, Zhenhua Dai.
      Background: Ferroptosis is an emerging type of regulated cell death and associated with antitumoral therapy, while some microRNAs have been shown to regulate the tumorigenesis and cancer progression. Meanwhile, polyphyllin I (PPI) has exhibited antitumoral effects by promoting cancer cell apoptosis and ferroptosis. However, it is unclear whether PPI induces cancer cell ferroptosis by regulating microRNAs. Methods: We used two gastric cancer cell lines (AGS and MKN-45) to set up a tumor model of the nude mice, which were then treated daily with PPI to measure the cancer growth in vitro and in vivo. Ferroptosis was measured using immunofluorescence staining and flow cytometric analysis according to levels of intracellular ROS, lipid ROS and ferrous ions. Moreover, NRF2 expression was measured by Western blotting. In some experiments, the mimics or inhibitors of miR-124-3p were used to further confirm its involvement in PPI-induced cancer cell ferroptosis. Results: Here we found that miR-124-3p mediated cancer ferroptosis and tumor repression induced by PPI since PPI increased miR-124-3p expression in gastric cancer cells and promoted their ferroptosis, whereas inhibition of miR-124-3p mostly abolished the effects of PPI on tumor growth, ferroptosis and NRF2 expression. Moreover, miR-124-3p mimics promoted cancer cell ferroptosis by downregulating NRF2 through directly targeting 3'-UTR region of NRF2, confirming a role for miR-124-3p in regulating PPI-induced ferroptosis. Conclusion: PPI exerts its antitumoral effects on the gastric cancer by promoting cell ferroptosis via regulating miR-124-3p. Our findings have clinical implications for cancer chemotherapy.
    Keywords:  MiR-124-3p; antitumor drug; ferroptosis; gastric cancer; polyphyllin I
    DOI:  https://doi.org/10.3389/fphar.2023.1285799
  4. J Cancer. 2023 ;14(18): 3387-3396
    Potentially Functional Genetic Variants in the NRF2 Signaling Pathway Genes are Associated With HBV-related Hepatocellular Carcinoma Survival.
    Rongbin Gong, Moqin Qiu, Ji Cao, Zihan Zhou, Yuying Wei, Qiuping Wen, Qiuling Lin, Xiaoxia Wei, Xiumei Liang, Yanji Jiang, Peiqin Chen, Junjie Wei, Shicheng Zhan, Yingchun Liu, Hongping Yu.
      The nuclear factor E2-related factor 2 (NRF2) signaling pathway is one of the most important cell defense pathways. However, it is unclear whether genetic variants in NRF2 signaling pathway genes are associated with the survival of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). In the present study, we utilized a new hypothesis-driven approach based on biological pathways to investigate the associations between 17919 single nucleotide polymorphisms (SNPs) in 137 NRF2 signaling pathway genes and the overall survival (OS) of 866 patients with HBV-related HCC. As a result, two independent SNPs with potential biological function were identified to be significantly associated with HBV-related HCC OS: [SLC2A9 rs28643326 T>C: hazard ratio (HR) = 0.74, 95% confidence interval (95% CI) = 0.62-0.89, P < 0.001 and SLC5A10 rs2472711 G>T: HR = 0.81, 95% CI = 0.71-0.93, P = 0.003, respectively]. The expression quantitative trait loci (eQTL) analysis further revealed that the rs28643326 C allele was significantly associated with increased levels of SLC2A9 mRNA expression (P < 0.001), and higher mRNA expression levels of SLC2A9 in adjacent normal liver tissues were associated with better survival. Although the association between the rs2472711 T allele and the mRNA expression of SLC5A10 was not statistically significant (P = 0.200), the fact that rs2472711 is located at the DNase I hypersensitivity site and is a marker for promoter and enhancer histones also suggests that it may have the function of regulating its corresponding gene expression. In conclusion, genetic variants of NRF2 signaling pathway genes may serve as potential prognostic biomarkers for HBV-related HCC and also provide a solid basis for further mechanistic exploration.
    Keywords:  HBV-related HCC; NRF2; OS; SNPs; eQTL
    DOI:  https://doi.org/10.7150/jca.88561
  5. Mol Cell. 2023 Nov 18. pii: S1097-2765(23)00917-6. [Epub ahead of print]
    Regulation of antioxidants in cancer.
    Fabio Hecht, Marco Zocchi, Fatemeh Alimohammadi, Isaac S Harris.
      Scientists in this field often joke, "If you don't have a mechanism, say it's ROS." Seemingly connected to every biological process ever described, reactive oxygen species (ROS) have numerous pleiotropic roles in physiology and disease. In some contexts, ROS act as secondary messengers, controlling a variety of signaling cascades. In other scenarios, they initiate damage to macromolecules. Finally, in their worst form, ROS are deadly to cells and surrounding tissues. A set of molecules with detoxifying abilities, termed antioxidants, is the direct counterpart to ROS. Notably, antioxidants exist in the public domain, touted as a "cure-all" for diseases. Research has disproved many of these claims and, in some cases, shown the opposite. Of all the diseases, cancer stands out in its paradoxical relationship with antioxidants. Although the field has made numerous strides in understanding the roles of antioxidants in cancer, many questions remain.
    Keywords:  NRF2; ROS; antioxidants; cancer; glutathione; oxidative stress
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.001
  6. Physiol Rep. 2023 Dec;11(23): e15879
    Umbelliferone attenuates cisplatin-induced acute kidney injury by inhibiting oxidative stress and inflammation via NRF2.
    Zhenle Yang, Ruofei Ning, Qianying Liu, Ruixian Zang, Suwen Liu, Shuzhen Sun.
      In this study, we investigated the nephroprotective effects of Umbelliferone (UMB) against cisplatin-induced acute kidney injury (AKI). C57BL/6J mice were treated with cisplatin via a single intraperitoneal injection (25 mg/kg) with or without UMB (40 mg/kg/day) by gavage. Renal function, apoptosis, oxidative stress, inflammation, and mitochondrial function were analyzed to evaluate kidney injury. In vitro, human proximal tubule epithelial cells were treated with cisplatin, with or without UMB, for 24 h. Western blotting and immunohistochemistry were performed to explore the mechanisms underlying the nephroprotective effects of UMB. Cisplatin-induced renal dysfunction, including increases in blood urea nitrogen, serum creatinine, and renal tubular injury indices (NGAL and KIM-1), were significantly attenuated by UMB treatment, along with renal phenotypic changes and renal tubular injury, as evidenced by improved renal histology. Moreover, NRF2 was activated by UMB pretreatment, along with the inhibition of oxidative stress and inflammatory response, as evidenced by decreased levels of antioxidant genes and inflammatory cytokines in cisplatin-induced AKI. Our results demonstrate that UMB can protect against cisplatin-induced nephrotoxicity, which is mediated by the NRF2 signaling pathway via antioxidant and anti-inflammatory activities, suggesting the clinical potential of UMB for the treatment of AKI.
    Keywords:  NRF2; UMB; cisplatin-induced AKI; inflammation; oxidative stress
    DOI:  https://doi.org/10.14814/phy2.15879
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