ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2024
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IF 10.8
Yanwei Wang,Jiahui Zhao,Yipeng Xu,Jing Miao,Keyu Pan,Yihan Li,Yong Chen,Xuesong Liu,Ailin Zhao,Jingyu Qin,Tengfei Xu,Mingliang Fang
Human exposure to polycyclic aromatic hydrocarbons (PAHs) as mutagenic and carcinogenic pollutants in the environment often occurs in the form of mixtures. Although the mixture effects of PAHs have been previously recognized, the toxicological mechanisms to explain them still remain quite unclear. This study combined metabolomics and chemical proteomics methods to comprehensively understand the mixture effects of a PAH mixture including benzo(a)anthracene (BaA), benzo(b)fluoranthene (BbF), benzo(a)pyrene (BaP), and chrysene (CHR). Among them, BaA has shown a strong synergistic effect with other PAHs. Interestingly, BaA alone is not a potent oxidative stress inducer in liver cells but dose-dependently amplifies oxidative damage caused by the PAH mixture. Global metabolomics analysis results revealed damage to the antioxidant glutathione synthesis, which was caused by the glutamine depletion caused by BaA in the mixture. Subsequently, the label-free chemical proteomics and cellular thermal shift analysis (CETSA) demonstrated that the PAH mixture altered the thermal shift of glutamine transporter SLC1A5. Furthermore, Western blotting and the isothermal titration calorimetry (ITC) interaction measurements showed nanomolar KD values between BaA and SLC1A5. Overall, this study showed that BaA synergistically contributed to PAH mixture induced oxidative damage by targeting SLC1A5 to inhibit glutamate transport into cells, resulting in the inhibition of glutathione synthesis.
研究领域:
环境毒理学
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代谢组学
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化学蛋白质组学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Yan Zhang,Yuanyuan Ren,Zhen Wang,Xi Zhang,Xiaofang Li,Yi Yu,Lu Qian,Yuyan Xiong
A high-fat diet and obesity significantly increase the risk of gastric cancer (GC), with persistent obesity contributing to a notable rise in GC incidence. However, the underlying molecular mechanisms remain largely unclear. In this study, we identified exosomal SLC1A5 (Exo-SLC1A5) as a novel senescence-associated secretory phenotype (SASP) factor that promotes GC malignancy. Exosomal SLC1A5 drives GC progression by suppressing ferroptosis in a GPX4-dependent manner. Mechanistically, in the context of obesity, senescent endothelial cells release exosomal SLC1A5, which engages EGFR on GC cells, triggering SRC phosphorylation at Tyr416 and subsequent YAP1 activation at Tyr357. This leads to YAP1 interaction with MYO1B to enhance the nuclear translocation of YAP1, and subsequent upregulation of GPX4, resulting in ferroptosis suppression and accelerated GC progression. In vivo, depletion of exosomal SLC1A5 from PA-induced senescent ECs attenuated GC tumor growth and metastasis in a xenograft mouse model. These findings reveal a novel mechanism by which exosomal SLC1A5 promotes GC progression through the EGFR/SRC/YAP1/GPX4 signaling axis. Targeting the Exo-SLC1A5/EGFR/SRC/YAP1/GPX4 axis may provide a therapeutic strategy for GC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2018
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IF 8.806
Cuifeng Wang,Jiamin Wu,Zhongjuan Wang,Zeping Yang,Zhi Li,Huihui Deng,Long Li,Xiao Peng,Min Feng
Many human cancer cells exhibit an oncogenetic-driven addiction to glutamine (Gln) as rapidly proliferating cancer cells consume Gln at a dramatically increased rate compared to normal cells. Tumor cells, therefore, compete with host cells for Gln, which causes Gln to flux from normal tissues to the tumor. We have developed and characterized a Gln macromolecular analog polyglutamine (PGS) for the delivery of gene regulators , such as siRNAs, in our previous works. Here, we hypothesize that PGS can utilize the Gln transporter SLC1A5 to specifically deliver therapeutic compounds to Gln-addicted cancer cells. Compared to human lung fibroblast HLF cells, cisplatin-resistant human lung adenocarcinoma A549/DDP cells significantly overexpress SLC1A5, which has a high binding affinity to PGS, as confirmed through molecular docking analysis. Due to the differences in Gln metabolism between malignant and normal cells, PGS/siRNA complexes were remarkably increased in cancer cells, especially when cells were deprived of Gln, which mirrors the conditions that are commonly found in a tumor microenvironment . Furthermore, we identified that chemical and genetic inhibition of Gln transporter SLC1A5 reduced the cellular internalization of PGS/siRNA complexes, suggesting a critical role for SLC1A5 in PGS uptake in cells. In turn, PGS upregulated SLC1A5 expression. Increased uptake of PGS complexes profoundly decreased intracellular Gln levels. Decreased Gln caused a moderate reduction in cell growth. To restore drug sensitivity and further enhance anti-tumor effects, the hybrid siRNAs anti-Survivin and anti-MDR1 (siSM), as model therapeutics, were administered through the PGS delivery system, which resulted in knockdown of Survivin and MDR1 and further sensitized cancer cells to the drug cisplatin (DDP). Since PGS complexes administered i.v. mostly accumulated in the lung parenchyma, a lung orthotopic tumor model was established to evaluate their inhibitory effects on tumors in the lungs. PGS/siSM comparably decreased the rate of tumor growth, while concurrent administration of PGS/siSM and DDP enhanced this effect and insignificantly improved life span. Consistent with our hypothesis, this study demonstrated that PGS mimicked Gln in the SLC1A5 pathway and selectively ferried therapeutics to Gln-addicted cancer cells. Our findings identified a new lung cancer targeting strategy based on Gln metabolism and can be used as a drug/gene delivery system.
研究领域:
肿瘤学
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药学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
INVESTIGATIONAL NEW DRUGS
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2022
·Vol. 40
·期 5
·977-989
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IF 3.651
Duan Zelin,Zhou Zhiyun,Lu Feifei,Zhang Yawen,Guo Xvqin,Gui Chunshan,Zhang Hongjian
Targeting tumor metabolic vulnerabilities such as “glutamine addiction” has become an attractive approach for the discovery of novel antitumor agents. Among various mechanisms explored, SLC1A5, a membrane transporter that plays an important role in glutamine cellular uptake, represents a viable target to interfere with tumor’s ability to acquire critical nutrients during proliferation. In the present study, a stably transfected HEK293 cell line with human SLC1A5 (HEK293-SLC1A5) was established for the screening and identification of small molecule SLC1A5 inhibitors. This in vitro system, in conjunction with direct measurement of SLC1A5-mediated L-glutamine-2,3,3,4,4-D 5 (substrate) uptake, was practical and efficient in ensuring the specificity of SLC1A5 inhibition. Among a group of diverse compounds tested, mianserin (a tetracyclic antidepressant) demonstrated a marked inhibition of SLC1A5-mediated glutamine uptake. Subsequent investigations using SW480 cells demonstrated that mianserin was capable of inhibiting SW480 tumor growth both in vitro and in vivo, and the in vivo antitumor efficacy was correlated to the reduction of glutamine concentrations in tumor tissues. Computational analysis revealed that hydrophobic interactions between SLC1A5 and its inhibitors could be a critical factor in drug design. Taken together, the current findings confirmed the feasibility of targeting SLC1A5-mediated glutamine uptake as a novel approach for antitumor intervention. It is anticipated that structural insights obtained based on homology modeling would lead to the discovery of more potent and specific SLC1A5 inhibitors for clinical development.
研究领域:
肿瘤学
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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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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Simeng Xiao,Yun Zhao,Zhiguo Chen,Yangkun Xiong,Dingmei Zhang,Gang Zhou,Cong Zhang
Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the cellular vital activities, has become a promising direction for HCC management. Celastrol is a terpenoids natural product isolated from the Tripterygium wilfordii Hook F. and catches attention for its multiple pharmacological activities including anti-HCC therapeutic potential. However, its effects in regulating glutamine metabolism to suppress HCC progression have not been investigated. In this study, Hep3B and HepG2 cells were used to investigate the inhibitory effects of celastrol on hepatoma cells. Subsequently, the biosafety and inhibitory effects of celastrol on tumor growth were investigated in a xenograft animal model of liver cancer. Our results showed that celastrol restrained the proliferation of hepatoma cells which was tightly associated with reduction of glutamine metabolic flux. Mechanistically, celastrol restricted glutamine uptake by inhibiting the SLC1A5 expression to reduce the content of glutamine metabolism intermediates in hepatoma cells thereby interrupting the energy source for cell proliferation. Consistently, similar results were observed in a transplanted HCC tumor mouse model. Interestingly, overexpression of SLC1A5 reversed the efficacy of celastrol in decreasing glutamine metabolic flux to suppress the malignant proliferation of hepatoma cells in vitro and in vivo . Overall, this study provides compelling evidence to demonstrate the efficacy of celastrol in inhibiting hepatocarcinogenesis by suppressing SLC1A5-mediated glutamine dependence, suggesting that celastrol as a natural active compound is expected to be developed as a therapeutic agent for HCC.
研究领域:
肿瘤学
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癌症生物学
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分子生物学
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药理学
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代谢学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Zhihong Wang,Taifeng Li,Ruisheng Li,Bo Cao,Shiyuan Wang,Xiaofei Fei,Chunyu Li,Guohui Li
Lung cancer is a major health concern and significant barrier to human well-being and social development. Although targeted therapy has shown remarkable progress in the treatment of lung cancer, the emergence of drug resistance has limited its clinical efficacy. Sijunzi Tang (SJZ) is a classical Chinese herbal formula known for tonifying qi and nourishing the lungs, has been recognized for its potential in lung cancer management. However, the underlying mechanism of its combined use with anti-cancer drugs remains unclear. Here, we investigated the anti-lung cancer efficacy and underlying mechanisms of the combination of gefitinib and SJZ in gefitinib-resistant human lung adenocarcinoma cells (PC-9/GR). We conducted in vitro and in vivo experiments using histopathology and targeted metabolomics approaches. Our results demonstrated that the combination of SJZ and gefitinib exhibited synergistic effects on tumor growth inhibition in PC-9/GR-bearing nude mice. Notably, the co-administration of SJZ and gefitinib synergistically promoted tumor cell apoptosis, potentially through the regulation of BAX and BCL-2 expression. Immunohistochemistry and western blot analysis found down-regulation of GLS, GS, and SLC1A5 expression in the co-administration group compared to the control and the individual treatment groups. Targeted metabolomics revealed significant alterations in the plasma glutamine metabolic markers glutamine, alanine, succinate, glutamate, and pyruvate. Of the glutamine metabolism markers measured in tumor tissues, glutamine and pyruvate demonstrated significant differences across the treatment groups. These findings suggest that administration of SJZ improves gefitinib resistance in the treatment of lung cancer without toxic effects. Moreover, SJZ may affect glutamine metabolism by regulating key targets involved in glutamine metabolism (SLC1A5, GLS, and GS) and modulating the levels of related metabolic markers, ultimately reducing gefitinib resistance.
研究领域:
肿瘤学
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药理学
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代谢组学
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中医
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2021
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IF 3.935
Zhongjian Chen,Yun Gao,Xiancong Huang,Yao Yao,Keke Chen,Su Zeng,Weimin Mao
Prognosis for esophageal squamous cell carcinoma (ESCC) is poor, so it is essential to develop a more complete understanding of the disease. The purpose of this study was to explore metabolic biomarkers and potential therapeutic targets for ESCC. An ultra-high-performance liquid chromatography coupled with high resolution mass (UPLC/MS)-based metabolomic analysis was performed in 141 ESCC cancerous tissue samples and 70 non-cancerous counterparts. The results showed that 41 differential metabolites were annotated in the training set, and 37 were validated in the test set. Single-metabolite-based receiver operating characteristic (ROC) curves as well as metabolite-based machine learning models, including Partial Least Squares (PLS), Support Vector Machine (SVM), and Random Forest (RF), were investigated for cancerous and non-cancerous tissue classification. Six most prevalent diagnostic metabolites—adenylsuccinic acid, UDP-GalNAc, maleylacetoacetic acid, hydroxyphenylacetylglycine, galactose, and kynurenine—showed testing predictive accuracies of 0.89, 0.95, 0.97, 0.89, 0.84, and 0.84, respectively. Moreover, the metabolite-based models (PLS, SVM, and RF) had testing predictive accuracies of 0.95, 0.95, and 1.00, respectively. Kaplan–Meier survival analysis and Cox proportional hazards regression analysis demonstrated that 2-hydroxymyristoylcarnitine (HR: 0.55, 95 % CI: 0.32 to 0.92), 3-hydroxyhexadecanoylcarnitine (HR: 0.49, 95 % CI: 0.29 to 0.83), and 2,3-Dinor-TXB1 (HR: 0.56, 95 % CI: 0.33 to 0.95) to be significantly associated with OS. Based on the observation of accumulation in amino acids, immunohistochemistry (IHC) staining revealed that the amino acid transporters SLC7A5/LAT1, SLC1A5/ASCT2, and SLC16A10/MCT10 were up-regulated in ESCC cancerous tissues when compared to non-cancerous equivalents. Consistently, the same panel of amino acids were downregulated in cells with SLC1A5 knockdown. Herein, it is concluded that this study not only identified several metabolites with diagnostic and/or prognostic value, but also provided accurate metabolite-based prediction models for ESCC tissue classification. Furthermore, the three up-regulated amino acid transporters were identified as potential therapeutic targets for ESCC, especially SLC1A5.
研究领域:
肿瘤学
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代谢组学
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生物信息学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
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