bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2024‒06‒09
nine papers selected by
Caner Geyik, Istinye University
  1. PPIA dictates NRF2 stability to promote lung cancer progression.
  2. GOLPH3 inhibits erastin-induced ferroptosis in colorectal cancer cells.
  3. Arsenic Trioxide Suppresses Angiogenesis in Non-small Cell Lung Cancer via the Nrf2-IL-33 Signaling Pathway.
  4. Hsa_circ_0096157 silencing suppresses autophagy and reduces cisplatin resistance in non-small cell lung cancer by weakening the Nrf2/ARE signaling pathway.
  5. Ursolic acid inhibits the proliferation of triple‑negative breast cancer stem‑like cells through NRF2‑mediated ferroptosis.
  6. Protective effects of silymarin in glioblastoma cancer cells through redox system regulation.
  7. Hernandezine acts as a CDK4 suppressor inhibiting tumor growth by the CDK4/PKM2/NRF2 axis in colon cancer.
  8. Chemopreventive effects of atractylenolide-III on mammary tumorigenesis via activation of the Nrf2/ARE pathway through autophagic degradation of Keap1.
  9. SWI/SNF family mutations in advanced NSCLC: genetic characteristics and immune checkpoint inhibitors' therapeutic implication.
  1. Nat Commun. 2024 Jun 03. 15(1): 4703
    PPIA dictates NRF2 stability to promote lung cancer progression.
    Weiqiang Lu, Jiayan Cui, Wanyan Wang, Qian Hu, Yun Xue, Xi Liu, Ting Gong, Yiping Lu, Hui Ma, Xinyu Yang, Bo Feng, Qi Wang, Naixia Zhang, Yechun Xu, Mingyao Liu, Ruth Nussinov, Feixiong Cheng, Hongbin Ji, Jin Huang.
      Nuclear factor erythroid 2-related factor 2 (NRF2) hyperactivation has been established as an oncogenic driver in a variety of human cancers, including non-small cell lung cancer (NSCLC). However, despite massive efforts, no specific therapy is currently available to target NRF2 hyperactivation. Here, we identify peptidylprolyl isomerase A (PPIA) is required for NRF2 protein stability. Ablation of PPIA promotes NRF2 protein degradation and blocks NRF2-driven growth in NSCLC cells. Mechanistically, PPIA physically binds to NRF2 and blocks the access of ubiquitin/Kelch Like ECH Associated Protein 1 (KEAP1) to NRF2, thus preventing ubiquitin-mediated degradation. Our X-ray co-crystal structure reveals that PPIA directly interacts with a NRF2 interdomain linker via a trans-proline 174-harboring hydrophobic sequence. We further demonstrate that an FDA-approved drug, cyclosporin A (CsA), impairs the interaction of NRF2 with PPIA, inducing NRF2 ubiquitination and degradation. Interestingly, CsA interrupts glutamine metabolism mediated by the NRF2/KLF5/SLC1A5 pathway, consequently suppressing the growth of NRF2-hyperactivated NSCLC cells. CsA and a glutaminase inhibitor combination therapy significantly retard tumor progression in NSCLC patient-derived xenograft (PDX) models with NRF2 hyperactivation. Our study demonstrates that targeting NRF2 protein stability is an actionable therapeutic approach to treat NRF2-hyperactivated NSCLC.
    DOI:  https://doi.org/10.1038/s41467-024-48364-4
  2. Cell Biol Int. 2024 Jun 02.
    GOLPH3 inhibits erastin-induced ferroptosis in colorectal cancer cells.
    Lihua Chen, Chunxiao Wang, Xiaojing Chen, Yuze Wu, Mingliang Chen, Xian Deng, Chengzhi Qiu.
      Ferroptosis is a novel form of programmed cell death and is considered to be a druggable target for colorectal cancer (CRC) therapy. However, the role of ferroptosis in CRC and its underlying mechanism are not fully understood. In the present study we found that a protein enriched in the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3), was overexpressed in human CRC tissue and in several CRC cell lines. The expression of GOLPH3 was significantly correlated with the expression of ferroptosis-related genes in CRC. The overexpression of GOLPH3 in Erastin-induced Caco-2 CRC cells reduced ferroptotic phenotypes, whereas the knockdown of GOLPH3 potentiated ferroptosis in HT-29 CRC cells. GOLPH3 induced the expression of prohibitin-1 (PHB1) and prohibitin-2 (PHB2), which also inhibited ferroptosis in Erastin-treated CRC cells. Moreover, GOLPH3 interacted with PHB2 and nuclear factor erythroid 2-related factor 2 (NRF2) in Caco-2 cells. These observations indicate that GOLPH3 is a negative regulator of ferroptosis in CRC cells. GOLPH3 protects these cells from ferroptosis by inducing the expression of PHB1 and PHB2, and by interacting with PHB2 and NRF2.
    Keywords:  GOLPH3; NRF2; PHB1; PHB2; colorectal cancer; ferroptosis
    DOI:  https://doi.org/10.1002/cbin.12190
  3. Anticancer Agents Med Chem. 2024 Jun 05.
    Arsenic Trioxide Suppresses Angiogenesis in Non-small Cell Lung Cancer via the Nrf2-IL-33 Signaling Pathway.
    Mingdong Wang, Jizhong Yin, Qianyu Han, Bing Li, Xuewei Zhao, Lei Xue.
      BACKGROUND: Non-Small Cell Lung Cancer (NSCLC) ranks as a leading cause of cancer-related mortality, necessitating the urgent search for cost-effective and efficient anti-NSCLC drugs. Our preliminary research has demonstrated that arsenic trioxide (ATO) significantly inhibits NSCLC angiogenesis, exerting anti-tumor effects. In conjunction with existing literature reports, the Nrf2-IL-33 pathway is emerging as a novel mechanism in NSCLC angiogenesis.OBJECTIVE: This study aimed to elucidate whether ATO can inhibit NSCLC angiogenesis through the Nrf2-IL-33 pathway.
    METHODS: Immunohistochemistry was employed to assess the expression of Nrf2, IL-33, and CD31 in tumor tissues from patients with NSCLC. DETA-NONOate was used as a nitric oxide (NO) donor to mimic high levels of NO in the tumor microenvironment. Western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay were utilized to evaluate the expression of Nrf2 and IL-33 in the NCI-H1299 cell line. Subcutaneous xenograft models were established in nude mice by implanting NCI-H1299 cells to assess the anti-tumor efficacy of ATO.
    RESULTS: High expression levels of Nrf2 and IL-33 were observed in tumor samples from patients with NSCLC, and Nrf2 expression positively correlated with microvascular density in NSCLC. In vitro, NO (released from 1mM DETA-NONOate) promoted activation of the Nrf2-IL-33 signaling pathway in NCI-H1299 cells, which was reversed by ATO. Additionally, both Nrf2 deficiency and ATO treatment significantly attenuated NOinduced IL-33 expression. In vivo, both ATO and the Nrf2 inhibitor ML385 demonstrated significant inhibitory effects on angiogenesis tumor growth.
    CONCLUSION: Nrf2-IL-33 signaling is usually activated in NSCLC and positively correlates with tumor angiogenesis. ATO effectively disrupts the activation of the Nrf2-IL-33 pathway in NSCLC and thus inhibits angiogenesis, suggesting its potential as an anti-angiogenic agent for use in the treatment of NSCLC.
    Keywords:  Arsenic trioxide; IL-33.; NSCLC; Nrf2; angiogenesis
    DOI:  https://doi.org/10.2174/0118715206288348240420174853
  4. Mol Biol Rep. 2024 Jun 01. 51(1): 703
    Hsa_circ_0096157 silencing suppresses autophagy and reduces cisplatin resistance in non-small cell lung cancer by weakening the Nrf2/ARE signaling pathway.
    Huasong Lu, Jinliang Kong, Shuangqi Cai, Hong Huang, Jing Luo, Lihua Liu.
      BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer morbidity and mortality worldwide, and new diagnostic markers are urgently needed. We aimed to investigate the mechanism by which hsa_circ_0096157 regulates autophagy and cisplatin (DDP) resistance in NSCLC.METHODS: A549 cells were treated with DDP (0 μg/mL or 3 μg/mL). Then, the autophagy activator rapamycin (200 nm) was applied to the A549/DDP cells. Moreover, hsa_circ_0096157 and Nrf2 were knocked down, and Nrf2 was overexpressed in A549/DDP cells. The expression of Hsa_circ_0096157, the Nrf2/ARE pathway-related factors Nrf2, HO-1, and NQO1, and the autophagy-related factors LC3, Beclin-1, and p62 was evaluated by qRT‒PCR or western blotting. Autophagosomes were detected through TEM. An MTS assay was utilized to measure cell proliferation. The associated miRNA levels were also tested by qRT‒PCR.
    RESULTS: DDP (3 μg/mL) promoted hsa_circ_0096157, LC3 II/I, and Beclin-1 expression and decreased p62 expression. Knocking down hsa_circ_0096157 resulted in the downregulation of LC3 II/I and Beclin-1 expression, upregulation of p62 expression, and decreased proliferation. Rapamycin reversed the effect of interfering with hsa_circ_0096157. Keap1 expression was lower, and Nrf2, HO-1, and NQO1 expression was greater in the A549/DDP group than in the A549 group. HO-1 expression was repressed after Nrf2 interference. In addition, activation of the Nrf2/ARE pathway promoted autophagy in A549/DDP cells. Moreover, hsa_circ_0096157 activated the Nrf2/ARE pathway. The silencing of hsa_circ_0096157 reduced Nrf2 expression by releasing miR-142-5p or miR-548n. Finally, we found that hsa_circ_0096157 promoted A549/DDP cell autophagy by activating the Nrf2/ARE pathway.
    CONCLUSION: Knockdown of hsa_circ_0096157 inhibits autophagy and DDP resistance in NSCLC cells by downregulating the Nrf2/ARE signaling pathway.
    Keywords:  Autophagy; Cisplatin; Hsa_circ_0096157; Non-small cell lung cancer; Nrf2/ARE signaling pathway
    DOI:  https://doi.org/10.1007/s11033-024-09552-z
  5. Oncol Rep. 2024 Jul;pii: 94. [Epub ahead of print]52(1):
    Ursolic acid inhibits the proliferation of triple‑negative breast cancer stem‑like cells through NRF2‑mediated ferroptosis.
    Xinhua Yang, Beibei Liang, Lisha Zhang, Mingzhu Zhang, Ming Ma, Lijuan Qing, Hao Yang, Gang Huang, Jian Zhao.
      Ursolic acid (UA), a pentacyclic triterpenoid that has been found in a broad variety of fruits, spices and medicinal plants, has various biological effects such as reducing inflammation, protecting cells from damage, and preserving brain function. However, its impact on ferroptosis in cancer stem‑like cells remains unexplored. The present study investigated the effect of UA on MDA‑MB‑231 and BT‑549 cell‑derived triple‑negative breast CSCs (BCSCs) and its potential ferroptosis pathway. The effects of ferroptosis on BCSCs were demonstrated by the detection of ferroptosis‑related indexes including the intracellular level of glutathione, malondialdehyde, reactive oxygen species and iron. The effects of UA on the biological behaviors of BCSCs were analyzed by Cell Counting Kit‑8, stemness indexes detection and mammosphere formation assay. The mechanism of UA induction on BCSCs was explored by reverse transcription‑quantitative PCR and western blotting. BALB/c‑nude mice were subcutaneously injected with MDA‑MB‑231‑derived BCSCs to establish xenograft models to detect the effects of UA in vivo. The results revealed that BCSCs have abnormal iron metabolism and are less susceptible to ferroptosis. UA effectively reduces the stemness traits and proliferation of BCSCs in spheroids and mice models by promoting ferroptosis. It was observed that UA stabilizes Kelch‑like ECH‑associated protein 1 and suppresses nuclear factor erythroid‑related factor 2 (NRF2) activation. These findings suggested that the ability of UA to trigger ferroptosis through the inhibition of the NRF2 pathway could be a promising approach for treating BCSCs, potentially addressing metastasis and drug resistance in triple‑negative breast cancer (TNBC). This expands the clinical applications of UA and provides a theoretical basis for its use in TNBC treatment.
    Keywords:  CSCs; NRF2 pathways; TNBC; UA; ferroptosis
    DOI:  https://doi.org/10.3892/or.2024.8753
  6. Mol Biol Rep. 2024 Jun 04. 51(1): 723
    Protective effects of silymarin in glioblastoma cancer cells through redox system regulation.
    Sara Zarei Shandiz, Bahareh Erfani, Seyed Isaac Hashemy.
      BACKGROUND: Glioblastoma multiforme, a deadly form of brain tumor, is characterized by aggressive growth and poor prognosis. Oxidative stress, a disruption in the balance between antioxidants and oxidants, is a crucial factor in its pathogenesis. Silymarin, a flavonoid extracted from milk thistle, has shown therapeutic potential in inhibiting cancer cell growth, promoting apoptosis, and reducing inflammation. It also regulates oxidative stress. This study aims to investigate the regulatory effects of silymarin on oxidative stress parameters, especially the transcription factor Nrf2 and its related enzymes in GBM cancer cells, to develop a new anti-cancer compound with low toxicity.METHODS AND RESULTS: First, the cytotoxicity of silymarin on U-87 MG cells was investigated by MTT and the results showed an IC50 of 264.6 μM. Then, some parameters of the redox system were measured with commercial kits, and the obtained results showed that silymarin increased the activity of catalase and superoxide dismutase enzymes, as well as the total antioxidant capacity levels; while the malondialdehyde level that is an indicator of lipid peroxidation was decreased by this compound. The expression level of Nrf2 and HO-1 and glutaredoxin and thioredoxin enzymes were checked by real-time PCR method, and the expression level increased significantly after treatment.
    CONCLUSIONS: Our findings suggest that silymarin may exert its cytotoxic and anticancer effects by enhancing the Nrf2/HO-1 pathway through antioxidant mechanisms in U-87 MG cells.
    Keywords:  Antioxidant; Glioblastoma multiforme; Nrf2 pathway; Oxidative stress; Silymarin
    DOI:  https://doi.org/10.1007/s11033-024-09658-4
  7. Phytomedicine. 2024 May 28. pii: S0944-7113(24)00433-1. [Epub ahead of print]131 155775
    Hernandezine acts as a CDK4 suppressor inhibiting tumor growth by the CDK4/PKM2/NRF2 axis in colon cancer.
    Jun-Lin Lv, Yu-Shan Ren, Yu-Jun Tan, Ting Chu, Xin-Yue Cao, Huai-Yuan Liu, Ru Ma, Han Zhang, Qiu-Sheng Zheng, Gui-Cheng Dong, Jie Li.
      BACKGROUND: The cyclin-dependent kinase 4 (CDK4) interacts with its canonical and non-canonical substrates modulating the cell cycle in tumor cells. However, the potential substrates and the beyond-cell-cycle-regulated functions of CDK4 in colon cancer (CC) are still unknown. Hernandezine (HER) is previously verified to induce G0/G1 phase arrest and autophagic cell death in human cancer cells, which implies that HER might target G0/G1 phase-related proteins, including CDK4.PURPOSE: The present study tried to investigate the glycolytic metabolism and oxidative stress functions of CDK4 in colon cancer. Furthermore, the inhibitory effects and potential binding sites of HER on CDK4, as well as its anti-tumor activity were investigated in CC cells.
    METHODS: The mass spectrometry assay was performed to identify potential endogenous substrates of CDK4 and the correlation between glycolytic metabolic rate and CDK4 level in COAD patient tissues. Meanwhile, after inhibiting the activity or the expression of CDK4, the binding capacity of CDK4 to PKM2 and NRF2 and the latter two protein distributions in cytoplasm and nucleus were detected in CC cells. In vitro, the regulatory effects of the CDK4-PKM2-NRF2 axis on glycolysis and oxidative stress were performed by ECAR, OCR, and ROS assay. The inhibitory effect of HER on CDK4 activity was explored in CC cells and the potential binding sites were predicted and testified in vitro. Furthermore, tumor growth inhibition of HER by suppressing the CDK4-PKM2-NRF2 axis was also investigated in vitro and in vivo.
    RESULTS: PKM2 and NRF2 were identified as endogenous substrates of CDK4 and, high-expressed CDK4 was associated with low-level glycolysis in COAD. In vitro, inactivated CDK4 facilitated CDK4-PKM2-NRF2 complex formation which resulted in 1) inhibited PKM2 activity and retarded the glycolytic rate; 2) cytoplasm-detained NRF2 failed to transcript anti-oxidative gene expressions and induced oxidant stress. Additionally, as a CDK4 inhibitor, HER developed triple anti-tumor effects including induced G0/G1 phase arrest, suppressed glycolysis, and disrupted the anti-oxidative capacity of CC cells.
    CONCLUSION: The results first time revealed that CDK4 modulated glycolytic and anti-oxidative capacity of CC cells via bound to its endogenous substrates, PKM2 and NRF2. Additionally, 140Asp145Asn amino acid sites of CDK4 were potential targets of HER. HER exerts anti-tumor activity by inhibited the activity of CDK4, promoted the CDK4-PKM2-NRF2 complex formation in the CC cells.
    Keywords:  Colon cancer; Cyclin-dependent kinase 4; Glycolysis; Hernandezine; Pyruvate kinase 2
    DOI:  https://doi.org/10.1016/j.phymed.2024.155775
  8. Biomed Pharmacother. 2024 Jun 03. pii: S0753-3322(24)00736-4. [Epub ahead of print]176 116852
    Chemopreventive effects of atractylenolide-III on mammary tumorigenesis via activation of the Nrf2/ARE pathway through autophagic degradation of Keap1.
    Fangyi Long, Pinghan Wang, Yu Ma, Xudong Zhang, Ting Wang.
      The incidence of breast cancer is increasing annually, making it a major health threat for women. Chemoprevention using natural, dietary, or synthetic products has emerged as a promising approach to address this growing burden. Atractylenolide-III (AT-III), a sesquiterpenoid present in various medicinal herbs, has demonstrated potential therapeutic effects against several diseases, including tumors, nonalcoholic fatty liver disease, and cerebral ischemic injury. However, its impact on breast cancer chemoprevention remains unexplored. In this study, we used an N-methyl-N-nitrosourea (NMU)-induced rat breast cancer model and 17β-estradiol (E2)-treated MCF-10A cells to evaluate the chemopreventive potential of AT-III on mammary tumorigenesis. AT-III inhibited mammary tumor progression, evidenced by reduced tumor volume and multiplicity, prolonged tumor latency, and the reversal of NMU-induced weight loss. Furthermore, AT-III suppressed NMU-induced inflammation and oxidative stress through the Nrf2/ARE pathway in breast cancer tissues. In vitro, AT-III effectively suppressed E2-induced anchorage-independent growth and cell migration in MCF-10A cells. Nrf2 knockdown attenuated the protective effects of AT-III, highlighting the pivotal role of Nrf2 in AT-III-mediated suppression of tumorigenesis. The mechanism involves the induction of Nrf2 expression by AT-III through the autophagic degradation of Kelch-like ECH-associated protein 1 (Keap1). Overall, the results of this study indicate that AT-III is a promising candidate for breast cancer chemoprevention and provide valuable insights into its molecular interactions and signaling pathways.
    Keywords:  Atractylenolide-III; Breast cancer; Chemoprevention; Nrf2/ARE pathway
    DOI:  https://doi.org/10.1016/j.biopha.2024.116852
  9. ESMO Open. 2024 Jun 03. pii: S2059-7029(24)01241-9. [Epub ahead of print]9(6): 103472
    SWI/SNF family mutations in advanced NSCLC: genetic characteristics and immune checkpoint inhibitors' therapeutic implication.
    L-L Pang, H-Q Zhou, Y-X Zhang, W-T Zhuang, F Pang, L-J Chen, J Liao, Y-H Huang, T-Q Mao, Z-H Mai, L Zhang, W-F Fang.
      BACKGROUND: SWItch/Sucrose NonFermentable (SWI/SNF) mutations have garnered increasing attention because of their association with unfavorable prognosis. However, the genetic landscape of SWI/SNF family mutations in Chinese non-small-cell lung cancer (NSCLC) is poorly understood. In addition, the optimal treatment strategy has not yet been determined.PATIENTS AND METHODS: We collected sequencing data on 2027 lung tumor samples from multiple centers in China to comprehensively analyze the genomic characteristics of the SWI/SNF family within the Chinese NSCLC population. Meanwhile, 519 patients with NSCLC from Sun Yat-sen University Cancer Center were enrolled to investigate the potential implications of immunotherapy on patients with SWI/SNF mutations and to identify beneficial subpopulations. We also validated our findings in multiple publicly available cohorts.
    RESULTS: Approximately 15% of Chinese patients with lung cancer harbored mutations in the SWI/SNF chromatin remodeling complex, which were mutually exclusive to the EGFR mutations. Patients with SWI/SNFmut NSCLC who received first-line chemoimmunotherapy had better survival outcomes than those who received chemotherapy alone (median progression-free survival: 8.70 versus 6.93 months; P = 0.028). This finding was also confirmed by external validation using the POPLAR/OAK cohort. SWI/SNFmut NSCLC is frequently characterized by high tumor mutational burden and concurrent TP53 or STK11/KEAP mutations. Further analysis indicated that TP53 and STK11/KEAP1 mutations could be stratifying factors in facilitating personalized immunotherapy and guiding patient selection.
    CONCLUSIONS: This study provides a step forward in understanding the genetic and immunological characterization of SWI/SNF genetic alterations. Moreover, our study reveals substantial benefits of immunotherapy over chemotherapy for SWI/SNF-mutant patients, especially the SWI/SNFmut and TP53mut subgroups.
    Keywords:  SWI/SNF; co-occurring mutation; immune checkpoint inhibitors; non-small-cell lung cancer
    DOI:  https://doi.org/10.1016/j.esmoop.2024.103472
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