Acta Biomaterialia
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2023
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IF 9.7
Jiawu Yu,Yuchen Zhang,Liqi Li,Yang Xiang,Xuemei Yao,Youbo Zhao,Kaiyong Cai,Menghuan Li,Zhongjun Li,Zhong Luo
Radiotherapy is a mainstream modality for breast cancer treatment that employs ionizing radiation (IR) to damage tumor cell DNA and elevate ROS stress, which demonstrates multiple clinically-favorable advantages including localized treatment and low invasiveness. However, breast cancer cells may activate the p53-mediated cell cycle regulation in response to radiotherapy to repair IR-induced cellular damage and facilitate post-treatment survival. F-Box and WD Repeat Domain Containing 7 (FBXW7) is a promoter of p53 degradation and critical nexus of cell proliferation and survival events. Herein, we engineered a cooperative radio-ferroptosis-stimulatory nanomedicine through coordination-driven self-assembly between ferroptosis-inducing Fe 2+ ions and FBXW7-inhibiting DNAzymes and further modification of tumor-targeting dopamine-modified hyaluronic acid (HA). The nanoassembly could be selectively internalized by breast cancer cells and disintegrated in lysosomes to release the therapeutic payload. DNAzyme readily abolishes FBXW7 expression and stabilizes phosphorylated p53 to cause irreversible G2 phase arrest for amplifying post-IR tumor cell apoptosis. Meanwhile, the p53 stabilization also inhibits the SLC7A11-cystine-GSH axis, which combines with the IR-upregulated ROS levels to amplify Fe 2+ -mediated ferroptotic damage. The DNAzyme-Fe-HA nanoassembly could thus systematically boost the tumor cell damaging effects of IR, presenting a simple and effective approach to augment the response of breast cancer to radiotherapy. Statement of Significance To overcome the intrinsic radioresistance in breast cancer, we prepared co-assembly of Fe 2+ and FBXW7-targeted DNAzymes and modified surface with dopamine conjugated hyaluronic acid (HA), which enabled tumor-specific FBXW7-targeted gene therapy and ferroptosis therapy in IR-treated breast cancers. The nanoassembly could be activated in acidic condition to release the therapeutic contents. Specifically, the DNAzymes could selectively degrade FBXW7 mRNA in breast cancer cells to simultaneously induce accumulation of p53 and retardation of NHEJ repair , eventually inducing irreversible cell cycle arrest to promote apoptosis. The p53 stabilization would also inhibit the SLC7A11/GSH/GPX4 axis to enhance Fe 2+ mediated ferroptosis. These merits could act in a cooperative manner to induce pronounced tumor inhibitory effect, offering new approaches for tumor radiosensitization in the clinics.
研究领域:
肿瘤学
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分子生物学
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纳米医学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
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IF 5.8
Xiaoxiang Mo,Xiaoju Shen,Xiaocheng Mo,Fei Yu,Weidan Tan,Zhihua Deng,Jingchuan He,Zhuo Luo,Zhiquan Chen,Jie Yang
Small cell lung cancer (SCLC) is the most malignant lung cancer with rapid growth and early metastasis, but still lacks effective targeted therapies to improve the prognosis. Here, we demonstrated that a novel oncogenic protein, cell migration inducing hyaluronic binding protein (CEMIP), was robustly overexpressed in SCLC tissues than that in noncancerous tissues and high expression of CEMIP predicted poor outcomes in clinical specimens and in large sample size cohorts from public databases (GEPIA 2 and CPTAC). Liquid chromatography mass spectrometry (LC-MS) and in vitro/in vivo functional assays indicated that CEMIP contributed to the proliferation by increasing glutamine consumption and their metabolites (glutamate and glutathione) levels in SCLC cells. Moreover, the addition of a GLS1 inhibitor CB-839 dramatically reduced CEMIP-induced SCLC cell proliferation . Mechanistically, beyond as a scaffold protein , CEMIP facilitates glutamine-dependent cell proliferation through inhibiting c-Myc ubiquitination and increasing c-Myc stabilization and nuclear accumulation via hindering the interaction between FBXW7 (a E3 ubiquitin ligase) and its target substrate c-Myc. Taken together, our findings reveal a novel oncogenic role of CEMIP in sustaining SCLC growth via FBXW7/c-Myc-dependent axis, and provide new evidence that inhibition of CEMIP might be a potential therapeutic strategy for the treatment of SCLC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Se-Ruo Li,Ning-Ning Kang,Rong-Rong Wang,Meng-Die Li,Li-Hong Chen,Peng Zhou,De-Xiang Xu,Hui Zhao,Lin Fu
Our previous study revealed that 1-nitropyrene (1-NP) exposure evoked pulmonary fibrosis in mice. However, the exact mechanism remained elusive. We found that 1-NP induced telomere damage and cellular senescence in mice lungs, and two alveolar epithelial cells lines. 1-NP downregulated telomere repeat binding factor 2 (TRF2), and upregulated FBXW7. Mechanistically, 1-NP-caused TRF2 ubiquitination and proteasomal degradation depended on E3 ubiquitin ligase activity of FBXW7. Moreover, 1-NP upregulated FBXW7 m6A modification via an ALKBH5-YTHDF1-dependent manner. Further analysis suggested 1-NP promoted ALKBH5 SUMOylation and subsequent proteasomal degradation. Additionally, 1-NP evoked mitochondrial reactive oxygen species (mtROS) overproduction. Mito-TEMPO, a mitochondrial-targeted antioxidant, mitigated 1-NP-caused mtROS overproduction, ALKBH5 SUMOylation, FBXW7 m6A modification, TRF2 degradation, cellular senescence, and pulmonary fibrosis. Taken together, mtROS-initiated ALKBH5 SUMOylation and subsequent FBXW7 m6A modification is indispensable for TRF2 degradation and cellular senescence in alveolar epithelial cells during 1-NP-induced pulmonary fibrosis. Our study provides target intervention measures towards 1-NP-evoked pulmonary fibrosis. Environmental Implication 1-nitropyrene (1-NP) is a representative of nitro polycyclic aromatic hydrocarbon compound that can be formed during the insufficient combustion of organic substances like coal, oil, gas, and tobacco. Moreover, mounting researches have revealed that 1-NP can cause various respiratory system diseases, inclusive of acute lung injury, chronic obstructive pulmonary disease, and allergic asthma. The current research provides evidence that exposure to 1-NP induces pulmonary fibrosis through evoking telomere damage and cellular senescenc. What’s more, Mito-TEMPO, a mitochondrial-targeted antioxidant, can mitigate 1-NP-caused cellular senescence and pulmonary fibrosis. Our study provides target intervention measures towards 1-NP-evoked pulmonary fibrosis.
研究领域:
毒理学
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肺科学
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细胞生物学
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分子生物学
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环境健康
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PubMed
高影响因子
INFLAMMATION
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2023
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IF 5.1
Xing Zeyu,Zhen Yanhua,Chen Jie,Du Mingyang,Li Dongdong,Liu Ruyin,Zheng Jiahe
Atherosclerosis (AS), characterized by a maladaptive inflammatory response, is one of the most common causes of death among the elderly. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, has been reported to play a pro-inflammatory role in various pathological processes by regulating the nuclear translocation of pro-inflammatory transcription factors. However, the function of KPNA2 in AS remains unknown. ApoE −/− mice were fed high-fat diets for 12 weeks to establish an AS mice model. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to establish an AS cell model. We found that KPNA2 was upregulated in the aortic roots of atherosclerotic mice and LPS-stimulated cells. KPNA2 knockdown inhibited LPS-induced secretion of pro-inflammatory factors and monocyte-endothelial adhesion in HUVECs, whereas KPNA2 overexpression exerted the opposite effects. p65 and interferon regulatory factor 3 (IRF3), the transcription factors known to regulate the transcription of pro-inflammatory genes, interacted with KPNA2, and their nuclear translocations were blocked following KPNA2 silencing. Furthermore, we found that KPNA2 protein level was decreased by E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7), which was downregulated in the atherosclerotic mice. FBXW7 overexpression induced ubiquitination with subsequent proteasomal degradation of KPNA2. Meanwhile, the effects of KPNA2 deficiency on atherosclerotic lesions were further confirmed by in vivo experiments. Taken together, our study indicates that KPNA2 downregulation, regulated by FBXW7, may alleviate endothelial dysfunction and related inflammation in the progression of AS by suppressing the nuclear translocation of p65 and IRF3.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
Translational Research
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2026
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IF 6.1
Lu Han,Guo-Yuan Lin,Shao-Jie Chen,Qing-Xiu Zhang,Hua-Yue Wu,Tao Huang,Fan Lu,Hong-Fei Pu,Jing-Lin Wang,Tao Ran,Gao-Liang Zou,Jian-Chao Li,Ya Zhang,Xue-Ke Zhao
Liver fibrosis is marked by hepatic stellate cell (HSC) activation and increased glucose consumption. Focal adhesion kinase (FAK) upregulates c-Myc expression in HSCs, promoting aerobic glycolysis. This study explores how FAK promotes HSC activation and glycolysis via TRIM25. Immunohistochemistry (IHC) and Western blotting assessed the expression of FAK, TRIM25, FBXW7, c-Myc, and glycolysis-related proteins in human liver tissues and mouse models. Protein interactions were identified by co-immunoprecipitation (Co-IP) and LC-MS, and FAK and TRIM25 localization was observed by immunofluorescence. FAK inhibition reduced LX-2 cell activation, migration, and glycolysis. Co-IP and immunofluorescence confirmed FAK-TRIM25 interaction. FAK inhibits FBXW7-mediated c-Myc ubiquitination and enhances glycolysis by binding TRIM25’s RING, B-BOX, and SPRY regions. Inhibition of FAK improved liver fibrosis and glycolysis. FAK promotes HSC glycolysis through TRIM25 interaction, and its inhibition mitigates liver fibrosis, suggesting a potential therapeutic target.
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 5.6
Changfu Zhang,Haichun Li,Yushuai Gao,Kaiyuan Deng,Rongjun Qian
Glioma, a highly lethal and common malignant tumor of the central nervous system, is characterized by its aggressive invasive behavior. Tumor-associated macrophage (TAM) represent the most abundant infiltrating immune cell population in the glioma microenvironment and play a critical role in gliomagenesis and progression. Although A-kinase anchoring protein 13 (AKAP13) has been implicated in other cancers, its specific role in glioma progression and TAM infiltration remains unclear. In this study, we identify AKAP13 is significantly upregulated in glioma tissues and associated with poor patient survival. Functionally, AKAP13 silencing inhibited glioma cell invasion and TAM recruitment in both in vitro and in vivo models. Mechanistically, AKAP13 drives tumor progression by enhancing YAP expression and nuclear translocation, which subsequently upregulates the TAM-recruiting chemokines CSF1 and CCL2. We further identified F-box and WD repeat domain-containing 7 (FBXW7) as an upstream regulator that promotes ubiquitin-mediated degradation of AKAP13. Together, our findings reveal a novel FBXW7/AKAP13/YAP/chemokine signaling axis that promotes glioma pathogenesis through both tumor-autonomous invasion and TAM recruitment, highlighting a promising therapeutic target for this lethal malignancy.
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PubMed
高影响因子
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