RESUMO
Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/- mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.
Assuntos
Colite , Imunidade nas Mucosas , Camundongos Knockout , Mitocôndrias , Proteínas Nucleares , Nucleofosmina , Fosforilação Oxidativa , Animais , Mitocôndrias/metabolismo , Camundongos , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Humanos , Colite/imunologia , Colite/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Interleucina 22 , Imunidade Inata , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Sulfato de Dextrana , Masculino , Interleucinas/metabolismo , Interleucinas/genética , Interleucinas/imunologia , FemininoRESUMO
Introduction: Nuclear respiratory factor 1 (NRF1) is an important regulator involved in mitochondrial biogenesis and energy metabolism. However, the specific mechanism of NRF1 in anoikis and epithelial-mesenchymal transition (EMT) remains unclear. Methods: We examined the effect of NRF1 on mitochondria and identified the specific mechanism through transcriptome sequencing, and explored the relationships among NRF1, anoikis, and EMT. Results: We found that upregulated NRF1 expression led to increased mitochondrial oxidative phosphorylation (OXPHOS) and ATP generation. Simultaneously, a significant amount of ROS is generated during OXPHOS. Alternatively, NRF1 upregulates the expression of ROS-scavenging enzymes, allowing tumor cells to maintain low ROS levels and promoting anoikis resistance and EMT. We also found that exogenous ROS was maintained at a low level by NRF1 in breast cancer cells. Conclusion: our study provides mechanistic insight into the function of NRF1 in breast cancer, indicating that NRF1 may serve as a therapeutic target for breast cancer treatment.
Assuntos
Anoikis , Neoplasias da Mama , Transição Epitelial-Mesenquimal , Fator 1 Nuclear Respiratório , Humanos , Feminino , Linhagem Celular Tumoral , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/genética , Fator 1 Nuclear Respiratório/genética , Fator 1 Nuclear Respiratório/metabolismo , Fosforilação Oxidativa , Homeostase , Anoikis/genética , Trifosfato de Adenosina/biossíntese , Mitocôndrias/metabolismo , Potencial da Membrana Mitocondrial , Espécies Reativas de Oxigênio/metabolismoRESUMO
Ferroptosis is one of the programmed modes of cell death that has attracted widespread attention recently and is capable of influencing the developmental course and prognosis of many tumors. Glioma is one of the most common primary tumors of the central nervous system, but effective treatment options are very limited. Ferroptosis plays a critical role in the glioma progression, affecting tumor cell proliferation, angiogenesis, tumor necrosis, and shaping the immune-resistant tumor microenvironment. Inducing ferroptosis has emerged as an attractive strategy for glioma. In this paper, we review ferroptosis-related researches on glioma progression and treatment.