bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2024–03–10
seven papers selected by
Caner Geyik, Istinye University
  1. Arenobufagin inhibits lung metastasis of colorectal cancer by targeting c-MYC/Nrf2 axis.
  2. Retraction: Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition.
  3. Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications.
  4. YES1 as a potential target to overcome drug resistance in EGFR-deregulated non-small cell lung cancer.
  5. [Clinicopathological and molecular characteristics of esophageal carcinoma with ductal differentiation: analysis of 17 cases].
  6. Impact of NDUFAF6 on breast cancer prognosis: linking mitochondrial regulation to immune response and PD-L1 expression.
  7. Outcomes in patients treated with frontline immune checkpoint inhibition (ICI) for advanced NSCLC with KRAS mutations and STK11/KEAP1 comutations across PD-L1 levels.
  1. Phytomedicine. 2024 Feb 21. pii: S0944-7113(24)00056-4. [Epub ahead of print]127 155391
    Arenobufagin inhibits lung metastasis of colorectal cancer by targeting c-MYC/Nrf2 axis.
    Mei Wang, Siyi Hu, Jiawang Yang, Liang Yuan, Limin Han, Feng Liang, Fenglin Zhang, Hailong Zhao, Yun Liu, Ning Gao.
       BACKGROUND: Colorectal cancer (CRC) is one of the commonest cancers worldwide. Metastasis is the most common cause of death in patients with CRC. Arenobufagin is an active component of bufadienolides, extracted from toad skin and parotid venom. Arenobufagin reportedly inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in various cancers. However, the mechanism through which arenobufagin inhibits CRC metastasis remains unclear.
    PURPOSE: This study aimed to elucidate the molecular mechanisms by which arenobufagin inhibits CRC metastasis.
    METHODS: Wound-healing and transwell assays were used to assess the migration and invasion of CRC cells. The expression of nuclear factor erythroid-2-related factor 2 (Nrf2) in the CRC tissues was assessed using immunohistochemistry. The protein expression levels of c-MYC and Nrf2 were detected by immunoblotting. A mouse model of lung metastasis was used to study the effects of arenobufagin on CRC lung metastasis in vivo.
    RESULTS: Arenobufagin observably inhibited the migration and invasion of CRC cells by downregulating c-MYC and inactivating the Nrf2 signaling pathway. Pretreatment with the Nrf2 inhibitor brusatol markedly enhanced arenobufagin-mediated inhibition of migration and invasion, whereas pretreatment with the Nrf2 agonist tert‑butylhydroquinone significantly attenuated arenobufagin-mediated inhibition of migration and invasion of CRC cells. Furthermore, Nrf2 knockdown with short hairpin RNA enhanced the arenobufagin-induced inhibition of the migration and invasion of CRC cells. Importantly, c-MYC acts as an upstream modulator of Nrf2 in CRC cells. c-MYC knockdown markedly enhanced arenobufagin-mediated inhibition of the Nrf2 signaling pathway, cell migration, and invasion. Arenobufagin inhibited CRC lung metastasis in vivo. Together, these findings provide evidence that interruption of the c-MYC/Nrf2 signaling pathway is crucial for arenobufagin-inhibited cell metastasis in CRC.
    CONCLUSIONS: Collectively, our findings show that arenobufagin could be used as a potential anticancer agent against CRC metastasis. The arenobufagin-targeted c-MYC/Nrf2 signaling pathway may be a novel chemotherapeutic strategy for treating CRC.
    Keywords:  Arenobufagin; Colorectal cancer; Metastasis; Nrf2; c-MYC
    DOI:  https://doi.org/10.1016/j.phymed.2024.155391
  2. Br J Pharmacol. 2024 Mar 04.
    Retraction: Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition.
      
    DOI:  https://doi.org/10.1111/bph.16346
  3. Cancer Drug Resist. 2024 ;7 8
    Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications.
    İlhan Yaylim, Melek Aru, Ammad Ahmad Farooqi, Mehmet Tolgahan Hakan, Brigitta Buttari, Marzia Arese, Luciano Saso.
      Oxidative stress is characterized by the deregulation of the redox state in the cells, which plays a role in the initiation of various types of cancers. The activity of galectin-1 (Gal-1) depends on the cell redox state and the redox state of the microenvironment. Gal-1 expression has been related to many different tumor types, as it plays important roles in several processes involved in cancer progression, such as apoptosis, cell migration, adhesion, and immune response. The erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress. In this review, we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells, particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway. The emerging evidence concerning the anti-apoptotic effect of Gal-1, together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress, supports the role of Gal-1 in the promotion of tumor cells proliferation, immuno-suppression, and anti-tumor drug resistance, thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression. Overall, a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents. Excitingly, although it is still understudied, the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis.
    Keywords:  Galectin-1; Nrf2; cancer drug resistance; oxidative stress
    DOI:  https://doi.org/10.20517/cdr.2023.79
  4. Arch Toxicol. 2024 Mar 05.
    YES1 as a potential target to overcome drug resistance in EGFR-deregulated non-small cell lung cancer.
    Eunjin Kook, JungYeol Lee, Do-Hee Kim.
      Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) such as gefitinib and osimertinib have primarily been used as first-line treatments for patients with EGFR-activating mutations in non-small cell lung cancer (NSCLC). Novel biomarkers are required to distinguish patients with lung cancer who are resistant to EGFR-TKIs. The aim of the study is to investigate the expression and functional role of YES1, one of the Src-family kinases, in EGFR-TKI-resistant NSCLC. YES1 expression was elevated in gefitinib-resistant HCC827 (HCC827/GR) cells, harboring EGFR mutations. Moreover, HCC827/GR cells exhibited increased reactive oxygen species (ROS) levels compared to those of the parent cells, resulting in the phosphorylation/activation of YES1 due to oxidation of the cysteine residue. HCC827/GR cells showed elevated expression levels of YES1-associated protein 1 (YAP1), NF-E2-related factor 2 (Nrf2), cancer stemness-related markers, and antioxidant proteins compared to those of the parent cells. Knockdown of YES1 in HCC827/GR cells suppressed YAP1 phosphorylation, leading to the inhibition of Bcl-2, Bcl-xL, and Cyclin D1 expression. Silencing YES1 markedly attenuated the proliferation, migration, and tumorigenicity of HCC827/GR cells. Dasatinib inhibited the proliferation of HCC827/GR cells by targeting YES1-mediated signaling pathways. Furthermore, the combination of gefitinib and dasatinib demonstrated a synergistic effect in suppressing the proliferation of HCC827/GR cells. Notably, YES1- and Nrf2-regulated genes showed a positive regulatory relationship in patients with lung cancer and in TKI-resistant NSCLC cell lines. Taken together, these findings suggest that modulation of YES1 expression and activity may be an attractive therapeutic strategy for the treatment of drug-resistant NSCLC.
    Keywords:  EGFR; NSCLC; Nrf2; TKI-resistance; YES1
    DOI:  https://doi.org/10.1007/s00204-024-03693-7
  5. Zhonghua Bing Li Xue Za Zhi. 2024 Mar 08. 53(3): 276-281
    [Clinicopathological and molecular characteristics of esophageal carcinoma with ductal differentiation: analysis of 17 cases].
    W J Jiang, S Ao, Y Y Cui, L Lu, C N Wang.
      Objective: To investigate the clinicopathological features and molecular genetic characteristics of esophageal carcinoma with ductal differentiation, and to summarize the experiences in its diagnosis and treatment. Methods: A total of 17 cases of esophageal carcinoma with ductal differentiation diagnosed in Ningbo Clinical Pathological Diagnosis Center, Ningbo, China from June 2011 to December 2022 were collected. The clinical information and pathological diagnosis was reviewed. The tumor histological features and immunohistochemical results were analyzed. The next-generation sequencing was performed to detect and analyze the gene mutations in tumor samples. Results: The 17 patients included in this study were 54-77 years old, with a median age of 66 years. There were 16 males and 1 female. Among them, 9 cases were mainly carcinoma with ductal differentiation. The squamous epithelium on the tumor's surface was accompanied by high-grade intraepithelial neoplasia. The tumor and atypical squamous epithelium were transitional, and the focus was accompanied by various proportions of squamous cell carcinoma component (less than 10%). The other 8 cases were mostly squamous cell carcinoma, basaloid squamous cell carcinoma or sarcomatoid carcinoma with various degrees of tumor specific differentiation and focal area of carcinoma with ductal differentiation (less than 10%). The tumor cells in the area with ductal differentiation were mainly arranged in small tubes, while the tubes showed a double-layer structure, including the inner cells and outer cells of the lumen. Immunohistochemical results showed that the outer cells of the tumorous tubules expressed p63, p40, CK5/6 and CK34βE12, while the inner cells expressed CK7. Compared with esophageal squamous cell carcinoma reported in the literature, the frequency of gene mutations such as MYC (P=0.002), TP63 (P=0.002), CDKN1C (P=0.002) and NFE2L2 (P=0.045) was significantly lower in this group of cases. At the signaling pathway level, the mutation frequency of NOTCH signaling pathway (P=0.041) was significantly higher, while the mutation frequencies of NRF2 pathway (P=0.013) and PI3K pathway (P=0.009) were significantly lower than that of esophageal squamous cell carcinoma. Conclusion: Esophageal carcinoma with ductal differentiation is a type of esophageal carcinoma with unique morphology, and its molecular changes are also significantly different from those of conventional esophageal squamous cell carcinoma.
    DOI:  https://doi.org/10.3760/cma.j.cn112151-20230720-00017
  6. Cancer Cell Int. 2024 Mar 08. 24(1): 99
    Impact of NDUFAF6 on breast cancer prognosis: linking mitochondrial regulation to immune response and PD-L1 expression.
    Baohong Jiang, Sixuan Wu, Lijun Zeng, Yuanbin Tang, Lunqi Luo, Lianjie Ouyang, Wenjie Feng, Yeru Tan, Yuehua Li.
       BACKGROUND: Breast cancer is a major global health concern, and there is a continuous search for novel biomarkers to predict its prognosis. The mitochondrial protein NDUFAF6, previously studied in liver cancer, is now being investigated for its role in breast cancer. This study aims to explore the expression and functional significance of NDUFAF6 in breast cancer using various databases and experimental models.
    METHODS: We analyzed breast cancer samples from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Human Protein Atlas (HPA) databases, supplemented with immunohistochemistry (IHC) staining to assess NDUFAF6 expression. A breast cancer cell xenograft mouse model was used to evaluate tumor growth, apoptosis, and NDUFAF6 expression. Survival probabilities were estimated through Kaplan-Meier plots and Cox regression analysis. A Protein-Protein Interaction (PPI) network was constructed, and differentially expressed genes related to NDUFAF6 were analyzed using GO, KEGG, and GSEA. The relationship between NDUFAF6 expression, immune checkpoints, and immune infiltration was also evaluated.
    RESULTS: NDUFAF6 was found to be overexpressed in breast cancer patients and in the xenograft mouse model. Its expression correlated with worse clinical features and prognosis. NDUFAF6 expression was an independent predictor of breast cancer outcomes in both univariate and multivariate analyses. Functionally, NDUFAF6 is implicated in several immune-related pathways. Crucially, NDUFAF6 expression correlated with various immune infiltrating cells and checkpoints, particularly promoting PD-L1 expression by inhibiting the NRF2 signaling pathway.
    CONCLUSION: The study establishes NDUFAF6 as a potential prognostic biomarker in breast cancer. Its mechanism of action, involving the inhibition of NRF2 to upregulate PD-L1, highlights its significance in the disease's progression and potential as a target for immunotherapy.
    Keywords:  Breast cancer; Immune infiltration; NDUFAF6; NRF2; PD-L1; Prognosis
    DOI:  https://doi.org/10.1186/s12935-024-03244-1
  7. Lung Cancer. 2024 Feb 24. pii: S0169-5002(24)00043-6. [Epub ahead of print]190 107510
    Outcomes in patients treated with frontline immune checkpoint inhibition (ICI) for advanced NSCLC with KRAS mutations and STK11/KEAP1 comutations across PD-L1 levels.
    Lova Sun, Elizabeth A Handorf, Yunyun Zhou, Hossein Borghaei, Charu Aggarwal, Jessica Bauman.
       INTRODUCTION: In patients with advanced NSCLC (aNSCLC), the impact of KRAS mutations (m) and comutations with STK11 and KEAP1 on outcomes across different PD-L1 levels remains incompletely understood. We aimed to investigate the frequency of KRAS mutations and comutations across PD-L1 levels, and the association between these mutations and survival, stratified by PD-L1 expression.
    METHODS: We conducted a nationwide cohort study of patients diagnosed with aNSCLC between 2016 and 2021 treated with frontline (chemo)immunotherapy, who underwent molecular genotyping including KRAS, STK11, and KEAP1. Real-world overall survival (OS) and progression-free survival (rwPFS) were estimated using Kaplan-Meier methodology. Cox multivariable regressions were used to evaluate the association between KRASm and survival across different PD-L1 strata, and to assess whether the association between KRASm and survival differed by PD-L1 level. Finally, within subgroups defined by PD-L1 expression, we used interaction terms to assess whether co-mutations with STK11 and KEAP1 moderated the association between KRAS mutation and survival.
    RESULTS: Of our 2593-patient cohort, 982 (37.9 %) were KRASm and 1611 (62.1 %) KRASwt. KRASm were enriched in the PD-L1 ≥50 % cohort (334/743, 45 %), but within patients with KRASm, co-mutations with STK11 and KEAP1 were enriched in the PD-L1 0 % cohort. KRASm was associated with significantly worse OS in the PD-L1 0 % cohort compared to the PD-L1 ≥50 % cohort (P for interaction = 0.008). On adjusted analyses stratified by PD-L1, KRASm was associated with worse survival only in the PD-L1 0 % group (OS HR 1.46, p = 0.001). KEAP1 and STK11 comutations were most strongly associated with worse OS in the PD-L1 0 % subgroup; patients with triple KRASm/KEAPm/STK11m PD-L1 0 % NSCLC experienced the worst outcomes.
    CONCLUSIONS: KRASm are associated with worse overall survival in PD-L1 negative NSCLC; however, this association is largely driven by comutations with STK11 and KEAP1, which are enriched in PD-L1 negative tumors.
    Keywords:  Immunotherapy; KRAS mutation; Non small cell lung cancer; Real world data
    DOI:  https://doi.org/10.1016/j.lungcan.2024.107510
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