JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2025
·Vol. 44
·期 1
·1-22
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IF 12.8
Zhu Susi,Zhang Xu,Liu Waner,Zhou Zhe,Xiong Siyu,Chen Xiang,Peng Cong
Background Melanoma, a highly aggressive and immunogenic skin cancer, often develops resistance to immunotherapy due to the immunosuppressive tumor microenvironment (TME). Although PD-1/PD-L1 inhibitors have significantly improved treatment outcomes, 30%-40% of patients exhibit no response or develop resistance. Mechanisms such as T-cell exhaustion within the TME limit therapeutic efficacy, necessitating the exploration of novel strategies to enhance immune responses. Methods This study evaluated the effects of Vinburnine (Vin) on melanoma cell proliferation, migration, invasion, apoptosis, and DNA damage through in vitro experiments. Transcriptomic analysis, Western blot, RT-PCR, dual-luciferase reporter assays, and ChIP experiments revealed the mechanism by which Vin regulates IL-24 via ATF3. The anti-tumor efficacy of Vin or IL-24 in combination with PD-1 monoclonal antibody, as well as their modulation of the tumor microenvironment, were validated through luciferase-mediated cytotoxicity assays and a murine melanoma model. Additionally, the correlation between IL-24 expression and patient prognosis or immunotherapy response was analyzed using public databases. Results This study delineates the phenotypic mechanisms by which vinburnine suppresses melanoma proliferation. Vin induces reactive oxygen species (ROS) generation, leading to DNA damage and the subsequent activation of the apoptotic cascade in melanoma cells. Additionally, vinburnine activates the P38/MAPK/ATF3 signaling axis, which drives the secretion of interleukin-24 (IL-24), enhancing the functionality of CD8 + T cells and modulating the tumor immune microenvironment to favor antitumor immunity. Notably, the combination of vinburnine with anti-PD-1 antibody therapy produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches. Conclusions These findings underscore the therapeutic potential of vinburnine, particularly when used in combination with immune checkpoint inhibitors, as a promising strategy for melanoma treatment.
研究领域:
肿瘤学
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免疫学
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药理学
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分子生物学
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细胞生物学
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生物化学
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转化医学
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PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
HuaFeng Zeng,YuXi Li,HongTing Zhao,Lin Chen,Lin Xu,ShaoYing Wang,YuFan Zhang,HaoChen Wang,ShuYun Huang,Yunqiang Xu,Chunnian You,Lei Sun,FengZhen Cui,Huanwen Tang
As a Class I human carcinogen ubiquitous in both industrial and household environments, benzene can cause hematopoietic damage even at low concentrations. However, its precise hematological toxicological molecular mechanism remains incompletely understood. Here, we demonstrate that hydroquinone (HQ), a benzene metabolite, induces ferroptosis and endoplasmic reticulum stress (ERs) in TK6 cells. Mechanistically, through a combination of RNA-Seq and database analyses, we identified ATF3 as a central molecular switch linking ERs to ferroptosis following HQ treatment, with its activation mediated by the PERK pathway. Using oxidative lipidomics, we further identified ALOX12 as a key lipid peroxidase involved in promoting ferroptosis. Moreover, chromatin immunoprecipitation sequencing (ChIP-Seq) and dual-luciferase reporter assays revealed that ATF3 directly binds to the ALOX12 promoter, triggering its transcriptional activation, which in turn accelerates lipid peroxidation and ultimately leads to ferroptosis. In a mouse model of benzene-induced hematotoxicity, knockdown of ATF3 effectively inhibits bone marrow ferroptosis and markedly ameliorates hematopoietic impairment. Importantly, our cohort study revealed that the higher of ATF3, ALOX12, MDA, and lower GSH/GSSG was significantly associated with hematotoxicity in workers exposed to benzene. Collectively, these findings suggest the ATF3-ALOX12 signal axis may represent promising biomarkers for monitoring early hematopoietic damage resulting from low-dose benzene exposure in environmentally exposed populations.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Jiaqi Li,Haoyu Chen,Zhengxin Lu,Yuanbiao Ma,Shanshan Li,Zhiyu Chen,Zhewen Deng,Qi Zhang,Bo Ma
Pristimerin (Pri), a natural triterpenoid from the Celastraceae family, exhibits potent anti-tumor and anti-inflammatory activities, yet its further development as a drug candidate is hampered by severe male reproductive toxicity and precise target cells and underlying mechanisms remain unclear. Therefore, this study aimed to identify the target cells and elucidate these mechanisms. In vivo , male mice were administered Pri to evaluate testicular injury, sperm quality, and BTB integrity, while LC-MS/MS was used to detect Pri distribution in testis, epididymis, and sperm, as well as its cellular uptake. In vitro , CCK-8 assessed cell viability, and inhibitor interventions identified contributions of distinct cell death pathways. Annexin V/PI, C11-BODIPY, and DCFH-DA/DHE were used to assess apoptosis and ferroptosis-related oxidative damage. Transcriptomics, RT-qPCR, Western blotting, and immunohistochemistry were performed to examine activation of the NUR77-ATF3-CHOP axis and molecular docking, MD simulations, CETSA, and siRNA-mediated knockdown validated direct NUR77 binding by Pri. Pri exposure induced testicular atrophy, BTB disruption, and sperm impairment, with accumulation in reproductive tissues. In vitro , Pri inhibited TM4 cell viability. Cell death was partially rescued by Z-VAD-FMK and Fer-1, indicating that Pri triggers apoptosis and ferroptosis. Mechanistically, Pri activated the NUR77-ATF3-CHOP axis and directly bound to NUR77, as confirmed by docking, MD simulations, and CETSA. Knockdown of NUR77 improved cell viability and suppressed Pri-induced ATF3 upregulation. Collectively, this study demonstrates that Pri directly targets NUR77, activating the NUR77-ATF3-CHOP axis and inducing both apoptosis and ferroptosis in Sertoli cells, leading to spermatogenesis dysfunction, thereby providing critical insights into Pri-induced testicular injury.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2024
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IF 4.5
Jiaojiao Chen,Shaoxia Wang,Huiyuan Zhang,Huixiang Li,Fei Wang,Yinglin Wang,Quan Zhao
Chemotherapy proves to be a successful method in treating primary breast cancer. Ironically, some commonly used chemotherapeutics may promote lung metastasis by increasing the activity of activating transcription factor 3 (ATF3). Thus, it is necessary to inhibit tumor metastasis while improving the anti-tumor effect of anti-cancer drugs. Herein, using curcumol (CUR) that possesses both anti-tumor and anti-metastasis activities as a model drug, we designed the nanogels based on temperature-responsive self-assembly and glutathione-triggered disassembly to address the abovementioned conflicts. Briefly, the copolymers (H-SS-P) were synthesized by coupling poly (N-isopropylacrylamide) onto hyaluronic acid (HA) via a disulfide bond-containing linker cystamine dihydrochloride . Copolymers could self-assemble into regular spherical nanogels at 37 °C with a 40-nm particle size for PNIPAAm's thermosensitivity. Hydrophobic CUR could be automatically entrapped into the core of nanogels. The H-SS-P@CUR nanogels could release drugs quickly upon exposure to the reductive tumor microenvironment . The superior efficacy of H-SS-P@CUR on inhibiting tumor growth was validated through assays both in vivo and in vitro . Moreover, nanogels may better down-regulate the expression of ATF3 protein by enhancing the cell uptake and tumor targeting of CUR, thereby significantly improving the anti-metastasis effect of CUR. This work not only proposed a novel strategy to simplify the preparation process of nanogels but also achieved effective drug delivery with enhanced anti-cancer and anti-metastasis effects.
研究领域:
药学
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癌症研究
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纳米技术
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药物递送系统
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DOI
高影响因子
Autophagy
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2022
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IF 13.391
Yuhua Zhang,Qiaojun Fang,Hongfeng Wang,Jieyu Qi,Shan Sun,Menghui Liao,Yunhao Wu,Yangnan Hu,Pei Jiang,Cheng Cheng,Xiaoyun Qian,Mingliang Tang,Wei Cao,Shang Xiang,Chen Zhang,Jianming Yang,Xia Gao,Zheng Ying,Renjie Chai
Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink1 expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss.Abbreviations: AAV: adeno-associated virus; ABR: auditory brainstem response; ATF3: activating transcription factor 3; ATOH1/MATH1: atonal bHLH transcription factor 1; BafA1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; COX4I1/COXIV: cytochrome c oxidase subunit 4I1; CTBP2/RIBEYE: C-terminal binding protein 2; DFP: deferiprone; EGFP: enhanced green fluorescent protein; FOXO3: forkhead box O3; GRIA2/GLUR2: glutamate receptor, ionotropic, AMPA2 (alpha 2); HC: hair cell; HSPD1/HSP60: heat shock protein 1 (chaperonin); IHC: inner hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MYO7A: myosin VIIA; OPTN: optineurin; OMM: outer mitochondrial membrane; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RT-qPCR: real-time quantitative polymerase chain reaction; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling; USP30: ubiquitin specific peptidase 30; XBP1: X-box binding protein 1.
研究领域:
细胞生物学
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神经科学
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耳科学
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PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
He Xiaojun,Long Qiang,Zhong Yiming,Zhang Yecen,Qian Bei,Huang Shixing,Chang Lan,Qi Zhaoxi,Li Lihui,Wang Xinming,Yang Xiaomei,Dong Gao Wei,Ye Xiaofeng,Zhao Qiang
Background: Ferroptosis has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury and can be inhibited or promoted by ATF3. Short-chain fatty acids (SCFAs) have shown benefits in various cardiovascular diseases with anti-inflammatory and antioxidant effects. However, the impact of SCFAs on ferroptosis in ischemic-stimulated cardiomyocytes remains unknown. This study aimed to investigate the effect of SCFAs on cardiomyocyte ferroptosis, the expression of ATF3, and its potential upstream regulators.Methods and results: The expression of ATF3, ferroptosis pathway geneset (FPG), and geneset of potential regulators for ATF3 (GPRA, predicted by the PROMO database) was explored in the public human myocardial infarction single-cell RNA-seq (sma) dataset. Cardiomyocyte data was extracted from the dataset and re-clustered to explore the FPG, ATF3, and GPRA expression patterns in cardiomyocyte subclusters. A dose-dependent toxic experiment was run to detect the suitable dose for SCFA treatment. The erastin-induced ferroptosis model and hypoxia-reoxygenation (H/R) model (10 h of hypoxia followed by 6 h of reoxygenation) were adopted to assess the effect of SCFAs via the CCK8 assay. Gene expression was examined via RT-PCR and western blot. Ferroptosis markers, including lipid peroxides and Fe2+, were detected using the liperfluo and ferroOrange probes, respectively. In the sma dataset, upregulated ferroptosis pathway genes were mainly found in the infarction-stimulated cardiac cells (border zone and fibrotic zone), particularly the cardiomyocytes and adipocytes. The ATF3 and some of its potential transcription factors (VDR, EGR3, PAX5, and SP1) can be regulated by SCFA. SCFA can attenuate erastin-induced lipid peroxidation in cardiomyocytes. SCFA treatment can also reverse erastin-induced Fe2+ increase but may strengthen the Fe2+ in the H/R model. We also precisely defined a ferroptosis subcluster of cardiomyocytes (CM09) that highly expressed FPG, ATF3, and GPRA.Conclusion: The ATF3 and the ferroptosis pathway are elevated in cardiomyocytes of injury-related cardiac regions (border zone, ischemic zone, and fibrotic zone). SCFA can attenuate cardiomyocyte ferroptosis and regulate the expression of ATF3. Our study offers novel insights into the potential targets of SCFAs in the cardiovascular system.
研究领域:
心脏病学
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分子生物学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
Autophagy
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2022
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IF 13.391
Jinjin Zhang,Haixia Wang,Hongbin Chen,Hongbo Li,Pan Xu,Bo Liu,Qian Zhang,Changjun Lv,Xiaodong Song
Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are major clinical manifestations of this disease; hence, blocking these processes is a practical treatment strategy. Here, highly upregulated LINC00941/lncIAPF was found to accelerate pulmonary fibrosis by promoting fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration. Assay for transposase-accessible chromatin using sequencing and chromatin immunoprecipitation experiments elucidated that histone 3 lysine 27 acetylation (H3K27ac) activated the chromosome region opening in the LINC00941 promoter. As a consequence, the transcription factor ATF3 (activating transcription factor 3) bound to this region, and LINC00941 transcription was enhanced. RNA affinity isolation, RNA immunoprecipitation (RIP), RNase-RIP, half-life analysis, and ubiquitination experiments unveiled that LINC00941 formed a RNA-protein complex with ELAVL1/HuR (ELAV like RNA binding protein 1) to exert its pro-fibrotic function. Dual-fluorescence mRFP-GFP-MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) adenovirus monitoring technology, human autophagy RT2 profiler PCR array, and autophagic flux revealed that the LINC00941-ELAVL1 axis inhibited autophagosome fusion with a lysosome. ELAVL1 RIP-seq, RIP-PCR, mRNA stability, and rescue experiments showed that the LINC00941-ELAVL1 complex inhibited autophagy by controlling the stability of the target genes EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), STAT1 (signal transducer and activators of transcription 1) and FOXK1 (forkhead box K1). Finally, the therapeutic effect of LINC00941 was confirmed in a mouse model and patients with IPF. This work provides a therapeutic target and a new effective therapeutic strategy related to autophagy for IPF.Abbreviations: ACTA2/a-SMA: actin alpha 2, smooth muscle; ATF3: activating transcription factor 3; ATG: autophagy related; Baf-A1: bafilomycin A1; BLM: bleomycin; CDKN: cyclin dependent kinase inhibitor; CLN3: CLN3 lysosomal/endosomal transmembrane protein, battenin; COL1A: collagen type I alpha; COL3A: collagen type III alpha; CXCR4: C-X-C motif chemokine receptor 4; DRAM2: DNA damage regulated autophagy modulator 2; ELAVL1/HuR: ELAV like RNA binding protein 1; EZH2: enhancer of zeste 2 polycomb repressive complex 2 subunit; FADD: Fas associated via death domain; FAP/FAPα: fibroblast activation protein alpha; FOXK1: forkhead box K1; FVC: forced vital capacity; GABARAP: GABA type A receptor-associated protein; GABARAPL2: GABA type A receptor associated protein like 2; IGF1: insulin like growth factor 1; IPF: idiopathic pulmonary fibrosis; LAMP: lysosomal associated membrane protein; lncRNA: long noncoding RNA; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPC1: NPC intracellular cholesterol transporter 1; RGS: regulator of G protein signaling; RPLP0: ribosomal protein lateral stalk subunit P0; ROC: receiver operating characteristic; S100A4: S100 calcium binding protein A4; SQSTM1/p62: sequestosome 1; STAT1: signal transducers and activators of transcription 1; TGFB1/TGF-β1: transforming growth factor beta 1; TNF: tumor necrosis factor; UIP: usual interstitial pneumonia; ULK1: unc-51 like autophagy activating kinase 1; VIM: vimentin.
研究领域:
呼吸病学
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分子生物学
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细胞生物学
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遗传学
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PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
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2016
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IF 3.025
Zixuan Liu,Qiong Shi,Xiufang Song,Yuxin Wang,Yawen Wang,Erqun Song,Yang Song
Tetrachlorobenzoquinone (TCBQ) is a downstream metabolite of pentachlorophenol (PCP). Previously, we demonstrated that TCBQ caused cytotoxicity due to mitochondrial-related apoptosis. Here, we confirmed the upregulation of death receptor 5 (DR5) followed by the construction of the death-inducing signaling complex (DISC). We also detected the activation of the caspase cascade, which was correlated with TCBQ-induced apoptotic cell death in PC12 cells. The upregulation of DR5 included transcriptional activation and de novo protein synthesis in response to TCBQ. We also identified the endoplasmic reticulum (ER) as a new target for the TCBQ challenge in PC12 cells. The protein kinase R-like ER kinase/eukaryotic translation initiation factor 2α (PERK/eIF2α)-mediated activating transcription factor 4 (ATF4)-ATF3-C/EBP homologous protein (CHOP) signaling pathway contributed to the process of TCBQ-induced ER stress. Blocking ATF4, ATF3, or CHOP signaling by gene silencing technology resulted in decreased cell apoptosis after exposure to TCBQ. Finally, NAC ameliorated TCBQ-induced apoptosis and ER stress, which illustrated that TCBQ-induced apoptosis is somehow ROS-dependent. In summary, this study provided important mechanistic insight into how TCBQ utilizes ER stress-related signaling to exhibit pro-apoptotic activity in PC12 cells.
研究领域:
毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
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