bims-nurfca 2023-04-09 papers

J Biochem Mol Toxicol. 2023 Apr 05. e23368

Eriodictyol regulated ferroptosis, mitochondrial dysfunction, and cell viability via Nrf2/HO-1/NQO1 signaling pathway in ovarian cancer cells.

Xiaokai Wang, Jun Chen, Hongyan Tie, Wei Tian, Yanli Zhao, Luying Qin, Siyan Guo, Qiufang Li, Chen Bao.

This study aimed to investigate the antitumor effect and the underlying molecular mechanism of eriodictyol on ovarian cancer cells. CaoV3 and A2780 were exposed to eriodictyol at different concentrations of 0-800 μM. Cell apoptosis and viability were determined by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay and Cell Counting Kit-8 (CCK-8) assay, respectively. Mitochondrial membrane potential was evaluated by flow cytometers with a JC-1 detection kit. Fe2+ content was evaluated using an iron assay kit. The section of tumor tissues was observed using hematoxylin-eosin (H&E) staining and nuclear factor erythroid 2-related factor 2 (Nrf2) expression was detected by immunohistochemistry (IHC) staining. Eriodictyol suppressed cell viability and induced cell apoptosis of CaoV3 and A2780 cells. Half maximal inhibitory concentration (IC50 ) value of CaoV3 at 24 and 48 h was (229.74 ± 5.13) μM and (38.44 ± 4.68) μM, and IC50 value of A2780 at 24 and 48 h was (248.32 ± 2.54) μM and (64.28 ± 3.19) μM. Fe2+ content and reactive oxygen species production were increased and protein levels of SLC7A11 and GPX4 were decreased by eriodictyol. Besides, eriodictyol reduced the ratio of JC-1 fluorescence ratio, glutathione and malondialdehyde contents but elevated Cytochrome C level. Nrf2 phosphorylation were obviously downregulated by eriodictyol. Finally, eriodictyol suppressed tumor growth, aggravated mitochondrial dysfunction and downregulated Nrf2 expression in tumor tissue in mice. Eriodictyol regulated ferroptosis, mitochondrial dysfunction and cell viability via Nrf2/HO-1/NQO1 signaling pathway in ovarian cancer.

Keywords: Nrf2; eriodictyol; ferroptosis; mitochondrial dysfunction; ovarian cancer

DOI: https://doi.org/10.1002/jbt.23368

Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00089-X. [Epub ahead of print]35(4): 722

NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.

DOI: https://doi.org/10.1016/j.cmet.2023.03.011

BMC Gastroenterol. 2023 Apr 06. 23(1): 114

CHFR promotes metastasis of human gastric carcinoma by activating AKT and ERK via NRF2- ROS axis.

Feiyun He, Bin Ye, Xiaomeng Wu, Jundi Pan, Jianbo Wang, Xiaojing Wang.

Tumor suppressor gene CHFR (The Checkpoint with Forkhead-associated and Ring finger domains) is a mitotic checkpoint and frequently hypermethylated in gastric cancer. Our previous study found CHFR played a certain extent pro-tumor function in gastric cancer. However, little is known about the underlying mechanism. In this study, we tried to further elucidate the role and mechanism for CHFR in gastric cancer (GC) by constructing CHFR stably expressed cell lines. As expected, the ectopic expression of CHFR slowed the cell proliferation in both two SGC-7901 and AGS cells, while significantly promoted the potential of cell migration and invasion. For the first time, our data indicated that stable expression of CHFR in SGC-7901 and AGS restrained cellular reactive oxygen species (ROS) generation and promoted the activation of AKT and ERK, two regulators of redox hemostasis. Furthermore, H2O2 treatment effectively elevated ROS level and reversed CHFR-induced cell invasion in stable SGC-7901 and AGS cells with the decreased phosphorylation of AKT and ERK. We also confirmed that CHFR exerted its function by promoting NRF2 expression. The most important is, the ectopic expression of CHFR significantly inhibited SGC-7901 cell-derived xenografts and obviously promoted lung metastasis of GC cell with NRF2, p-AKT and p-ERK increased. Taken together, our findings suggested that CHFR might take part in gastric cancer progression especially cancer metastasis by activating AKT and ERK via NRF2- ROS axis.

Keywords: AKT; CHFR; ERK; Gastric cancer; Metastasis; NRF2; ROS

DOI: https://doi.org/10.1186/s12876-023-02724-4

Biotechnol Genet Eng Rev. 2023 Apr 05. 1-20

Polyphyllin I induces apoptosis and autophagy in temozolomide-resistant glioma via modulation of NRF2 and MAPK-signaling activation.

Feifei Feng, Chao Sun, Xiao Wang, Huanan Zhang, Peng Cheng.

Glioma is the most prevailing main malignant neoplasm of the central nervous system with a miserable prognosis. Temozolomide is the first-line chemotherapy drug for glioma, but its drug resistance reduces temozolomide's clinical efficacy and becomes the principal cause of the failure of glioma chemotherapy. Polyphyllin I (PPI), an active component in Rhizoma Paridis, demonstrates favorable therapeutic actions in diverse malignant neoplasms. Its effect on temozolomide-resistant glioma, however, has not yet been characterized. Here, we demonstrated that polyphyllin I inhibited the proliferation of temozolomide-resistant glioma cell in a concentration-dependent manner. Further, we found that polyphyllin I had a direct effect on temozolomide-resistant glioma tumor cells and promote reactive oxygen species (ROS)-dependent apoptosis and autophagy via mitogen-activated protein kinase (MAPK)-signaling (p38-JNK) pathway. Mechanistically, we showed that polyphyllin I downregulate the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway, indicating that polyphyllin I may be an expected therapeutic strategy for patients with temozolomide-resistant gliomas.

Keywords: Temozolomide-resistant glioma; apoptosis; autophagy; nuclear factor erythroid 2-related factor-2; polyphyllin I

DOI: https://doi.org/10.1080/02648725.2023.2199553

Br J Cancer. 2023 Apr 03.

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

BACKGROUND: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring.
METHODS: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics.
RESULTS: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function.
CONCLUSIONS: Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.

DOI: https://doi.org/10.1038/s41416-023-02253-7