查找使用阿拉丁产品的科研文献

Proliferation and migration inhibition of adenoid cystic carcinoma cells through autophagy suppression via GLUT1 knockdown

Kan Liu,Jinlong Zhu,Yangyang Bao,Jin Fang,Shuihong Zhou,Jun Fan

Multiple studies have demonstrated a significant association between glucose transporter-1 (GLUT1) and the development and recurrence of adenoid cystic carcinoma (ACC). In this study, we investigated the impact of GLUT1 knockdown on adenoid cystic carcinoma. Our findings revealed that hypoxic conditions promoted the progression and autophagy of SACC83 and SACC-LM cell lines, an effect that was mitigated by GLUT1 knockdown. In vivo experiments showed that the combination of lentivirus-delivered GLUT1 shRNA and autophagy inhibitor chloroquine (CQ) produced the most substantial reduction in tumor volume, weight, Ki67 expression, and autophagy in tumor tissues. In conclusion, hypoxia facilitates ACC progression by upregulating GLUT1 expression. The suppression of GLUT1 expression and autophagy effectively inhibited ACC cell proliferation both in vitro and in vivo .

“Golgi-customized Trojan horse” nanodiamonds impair GLUT1 plasma membrane localization and inhibit tumor glycolysis

Bei Kang,Haobo Wang,Huaqing Jing,Yunsheng Dou,Sona Krizkova,Zbynek Heger,Vojtech Adam,Nan Li

Nutrient or energy deprivation, especially glucose restriction, is a promising anticancer therapeutic approach. However, establishing a precise and potent deprivation strategy remains a formidable task. The Golgi morphology is crucial in maintaining the function of transport proteins (such as GLUT1) driving glycolysis. Thus, in this study, we present a “Golgi-customized Trojan horse” based on tellurium loaded with apigenin (4′,5,7-trihydroxyflavone) and human serum albumin, which was able to induce GLUT1 plasma membrane localization disturbance via Golgi dispersal leading to the inhibition of tumor glycolysis. Diamond-shaped delivery system can efficiently penetrate into cells as a gift like Trojan horse, which decomposes into tellurite induced by intrinsically high H 2 O 2 and GSH levels. Consequently, tellurite acts as released warriors causing up to 3.8-fold increase in Golgi apparatus area due to the down-regulation of GOLPH3. Further, this affects GLUT1 membrane localization and glucose transport disturbance. Simultaneously, apigenin hinders ongoing glycolysis and causes significant decrease in ATP level. Collectively, our “Golgi-customized Trojan horse” demonstrates a potent antitumor activity because of its capability to deprive energy resources of cancer cells. This study not only expands the applications of tellurium-based nanomaterials in the biomedicine but also provides insights into glycolysis restriction for anticancer therapy.

Targeted blocking of EGFR and GLUT1 by compound H reveals a new strategy for treatment of triple-negative breast cancer and nasopharyngeal carcinoma

Chunmiao Wang,Zhaoquan Li,Honglan Zhai,Xiaoyan Shen,Fengming Li,Qiuping Zhang,Danrong Li,Huaxin Hou

Background Cytoplasmic epidermal growth factor receptor (EGFR) is overexpressed in both nasopharyngeal carcinoma (NPC) and triple-negative breast cancer (TNBC), while clinical outcome and prognosis vary greatly among patients treated with gefitinib, and all patients eventually develop resistance to this agent. Therefore, we propose a new concept for synthesizing multitarget compounds and reveal new therapeutic strategies for NPC and TNBC expressing EGFR. Methods Compound H was synthesized in our previous study. Molecular docking, and cell thermal shift assays (CETSAs) and drug affinity responsive target stability(DARTS) were used to confirm the binding of compound H to EGFR and GLUT1. Methylthiazolyldiphenyl-tetrazolium bromide(MTT), annexin V-PE assays, mitochondrial membrane potential (MMP) assays, and animal models were used to evaluate the inhibitory effect of compound H on TNBC cell lines. Energy metabolism tests, Western blotting, and immunofluorescence staining were performed to evaluate the synergistic effects on EGFR- and glucose transporter type 1(GLUT1)-mediated energy metabolism. Results Compound H can simultaneously act on the EGFR tyrosine kinase ATP-binding site and inhibit GLUT1-mediated energy metabolism, resulting in reductions in ATP, MMP, intra-cellular lactic acid, and EGFR nuclear transfer. The anti-tumor activity of compound H is significantly superior to the combination of GLUT1 inhibitor BAY876 and EGFR inhibitor gefitinib. Compound H has remarkable anti-proliferative effects on TNBC MDA-MB231 cells, and importantly, no obvious toxicity effects of compound H were found in vivo . Conclusions Synergistic effects of inhibition of EGFR- and GLUT1-mediated energy metabolism by compound H may present a new strategy for the treatment of TNBC and NPC.

Catalytic nanoreactors promote GLUT1-mediated BBB permeation by generating nitric oxide for potentiating glioblastoma ferroptosis

Ji Liu,Mengjuan Sun,Zhen Li,Hongguang Xiang,Qiyue Wang,Xiaofei Xin,Yan Shen

Glioblastoma, the most common malignant brain tumor with a poor prognosis, still needs to develop effective therapeutic strategies to prolong the patient’s survival. Inducing GBM tumor cell ferroptosis could be the specific assay to improve GBM therapeutic efficiency. In comparison, ferroptosis in GBM cells is limited by the low intracellular ferrous ion concentration and oxidation resistance. Herein, an MNP-based ferroptosis catalytic nanoreactor loading cisplatin (CMNP-Cis-Arg) was designed to evaluate their targeted delivery and therapeutic efficiency in GBM treatment. The ferroptosis catalytic nanoreactors achieved an effective GBM targeted transportation via chitosan oligosaccharide driven GLUT1-mediated BBB permeabilization and arginine-based tumor chemotactic. CMNP-Cis-Arg improves synergistically lipid oxidation in GBM cells by inducing ROS generation and depleting intracellular GSH. The MNPs elevate ROS levels in tumor cells by enhancing Fe 2+ -based Fenton reaction and the encapsulated cisplatin as a chemotherapy agent depleting GSH via inducing the DNA strand broken. Moreover, the CMNP-Cis-Arg further induces NO biosynthesis and generates ONOO – with high oxidability to increase lipid oxidation. The anti-GBM ability of the CMNP-Cis-Arg was evaluated both in vitro and in vivo, significantly inducing the GBM tumor cells’ apoptosis and reducing the tumor burden in an orthotopic mouse model. The investigation provided a novel ferroptosis catalytic nanoreactor and confirmed their anti-GBM efficiency in boosting tumor intracellular ferroptosis, suggesting a potential therapeutic strategy worth further investigating preclinically.

Apigenin ameliorates vascular injury in rats with high fructose-induced metabolic disturbance by inhibiting PI3K/AKT/GLUT1

Xiaofang Chen,Jianyang Tan,Lu Zhang,Yonggang Liu,Yahong Cheng,Qianying Zhang,Hong Ding

The abuse of fructose in daily diet may cause cardiovascular diseases that seriously threaten human health, and both safe and efficient solutions need to be developed. We investigated whether apigenin can prevent the harmful impact of excessive fructose on cardiovascular events. Based on the reduction of percentage of body fat and systolic pressure as well as the improvements in insulin resistance, lipid metabolism, and pathological injury to the thoracic aorta, we suggested that high levels of fructose cause vascular injury and metabolic disorders, which can be improved to some extent by using apigenin. Fundamentally, apigenin down-regulates levels of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and glucose transporter 1 (GLUT1), which increase with high concentrations of fructose. Moreover, the inflammation and asymmetric dimethylarginine (ADMA) levels increased in fructose group, but they decreased when the rats were fed with apigenin. The results suggest that PI3K/AKT/GLUT1 may have potential for alleviating cardiovascular injury, and apigenin can be an excellent candidate for supplements to ameliorate cardiovascular diseases related to high fructose consumption.

Cancer-associated fibroblast-derived extracellular vesicles loaded with GLUT1 inhibitor synergize anti-PD-L1 to suppress tumor growth via degrading matrix stiffness and remodeling tumor microenvironment

Yali Wu,Wenjuan Chen,Jingjing Deng,Xingyu Zhou,Jiangbin Chen,Zimo Yang,Xinghui Cao,Jiatong Liu,Qi Tan,E. Zhou,Minglei Li,Mengfei Guo,Yang Jin

Cancer immunotherapy has transformed cancer treatment, demonstrating the potential for lasting responses in multiple solid and hematologic malignancies and thus has revolutionized cancer treatment in clinic. However, the intricate tumor microenvironment (TME), characterized by a rigid extracellular matrix (ECM) and robust immunosuppressive environment, presents substantial hurdles to the effectiveness of cancer immunotherapy. Thus, cancer-associated fibroblasts (CAFs), the most abundant stromal cells that mediate ECM remodeling and participate in immune suppression, represent promising therapeutic targets for combination immunotherapy. In this study, by using and analyzing single-cell RNA-sequencing (scRNA-seq) in the public datasets, we have identified the elevated expression of glucose transporter 1 (GLUT1) in activated CAF subgroups within tumor sites compared to normal tissues. Moreover, the recent literature has also demonstrated that CAFs undergoing high metabolic levels have been identified to show a better response to immunotherapy. Furthermore, extracellular vesicles (EVs) secreted by CAFs remain unexplored, and their role in drug transport systems and targeting efficiency towards tumorous cells remains uninvestigated. Herein, we identified the elevated expression of glucose transporter 1 (GLUT1) as a prognostic indicator for cancer associated with poor prognosis and investigated the vulnerability of lung tumor cell lines and CAFs to pharmacological GLUT1 inhibition with BAY-876. Based on the possibility of targeting the intrinsic TME-associated metabolism by GLUT1 inhibition, we have firstly employed CAFs-derived extracellular vesicles (cEVs) as a carrier for targeted delivery of BAY-876 into GLUT1-high CAFs and tumor cells. The cEV-BAY-876 (cEV B6) treatment significantly resulted in glucose-rich, low-lactate TME, reversed the activated CAFs phenotype, enabled stromal reprogramming, decreased ECM stiffness and enhanced the infiltration of CD3 + CD8+ T cells in tumor core, thereby achieving an excellent anti-tumor efficiency. Moreover, cEV-B6 treatment synergized anti-programmed death ligand 1 (antiPD-L1) to reinvigorate the exhausted lymphocytes and exerted strong anticancer effects against mice lung tumors. Our study provides the first evidence that tumor stroma-specific therapies by targeting glucose metabolism present a promising strategy of remodeling the extracellular matrix to reverse CAFs into normal type and potentiate cytotoxic T lymphocytes (CTLs) infiltration thereby improving anticancer immunotherapy.

Isoginkgetin, a potential CDK6 inhibitor, suppresses SLC2A1/GLUT1 enhancer activity to induce AMPK-ULK1-mediated cytotoxic autophagy in hepatocellular carcinoma

Jie Yao,Shuming Tang,Chenyan Shi,Yunzhi Lin,Lanlan Ge,Qinghua Chen,Baoru Ou,Dongyu Liu,Yuyang Miao,Qiujie Xie,Xudong Tang,Jia Fei,Guangyi Yang,Jun Tian,Xiaobin Zeng

Isoginkgetin (ISO), a natural biflavonoid, exhibited cytotoxic activity against several types of cancer cells. However, its effects on hepatocellular carcinoma (HCC) cells and mechanism remain unclear. Here, we revealed that ISO effectively inhibited HCC cell proliferation and migration in vitro. LC3-II expression and autophagosomes were increased under ISO treatment. In addition, ISO-induced cell death was attenuated by treatment with chloroquine or knockdown of autophagy-related genes (ATG5 or ULK1). ISO significantly suppressed SLC2A1/GLUT1 (solute carrier family 2 member 1) expression and glucose uptake, leading to activation of the AMPK-ULK1 axis in HepG2 cells. Overexpression of SLC2A1/GLUT1 abrogated ISO-induced autophagy. Combining molecular docking with thermal shift analysis, we confirmed that ISO directly bound to the N terminus of CDK6 (cyclin-dependent kinase 6) and promoted its degradation. Overexpression of CDK6 abrogated ISO-induced inhibition of SLC2A1/GLUT1 transcription and induction of autophagy. Furthermore, ISO treatment significantly decreased the H3K27ac, H4K8ac and H3K4me1 levels on the SLC2A1/GLUT1 enhancer in HepG2 cells. Finally, ISO suppressed the hepatocarcinogenesis in the HepG2 xenograft mice and the diethylnitrosamine+carbon tetrachloride (DEN+CCl4)-induced primary HCC mice and we confirmed SLC2A1/GLUT1 and CDK6 as promising oncogenes in HCC by analysis of TCGA data and human HCC tissues. Our results provide a new molecular mechanism by which ISO treatment or CDK6 deletion promotes autophagy; that is, ISO targeting the N terminus of CDK6 for degradation inhibits the expression of SLC2A1/GLUT1 by decreasing the enhancer activity of SLC2A1/GLUT1, resulting in decreased glucose levels and inducing the AMPK-ULK1 pathway.

SOX2 promotes the glycolysis process to accelerate cervical cancer progression by regulating the expression of HK2

Ting Wang,Ruoan Jiang,Xueling Tang,Yingsha Yao,Peiyue Jiang

Background Cervical cancer is a major health burden in females worldwide, available studies indicated that sex-determining region Y-box 2 (SOX2) is closely related to the malignant phenotypes of multiple cancers including cervical cancer. However, the underlying mechanisms were blurred. Experimental Procedures A bioinformatics analysis was conducted to investigate the clinical correlation between SOX2 and cervical cancer. Transient transfection and lentivirus infection were utilized to achieve overexpression and knockdown of SOX2, respectively. The role of SOX2 in cervical cancer was confirmed by transwell and colony-forming assays. Immunoblot, dual-luciferase reporter, chromatin immunoprecipitation (ChIP), and biochemical experiments were employed. In addition, the xenograft models and immunohistochemistry (IHC) experiments were performed to validate the findings in vivo . Results The expression of SOX2 was significantly positively associated with the cell migration, invasion, and colony-forming abilities of cervical cancer cells. The following immunoblots revealed that the SOX2-induced malignant phenotypes might be related to the glycolysis process, since overexpressing SOX2 significantly promoted the hexokinase 2 (HK2) and glucose transporter-1 (GLUT1) expression, and increased the content of glucose and lactic acid. The further dual-luciferase reporter and ChIP experiments confirmed a binding relationship between SOX2 and HK2 promoter. More importantly, overexpressing SOX2 promoted tumor growth concomitant with a hyper-expression of HK2 and GLUT1 in xenograft tumor tissues, yet the treatment of glycolysis inhibitor significantly reversed those outcomes. Conclusion SOX2 promotes the malignant progression of cervical cancer by facilitating glycolysis.

Ameliorative effect of polydatin on hyperglycemia and renal injury in streptozotocin-induced diabetic rats

Lijuan Wang,Liji Huang,Nan Li,Junjun Miao,Wei Liu,Jiangyi Yu

To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1β, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin.  As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.

Increased glucose utilization is a targetable vulnerability to overcome drug resistance associated with neddylation blockade

Yueyang Guo,Zhuang Hu,Linyue Bai,Yanjun Tang,Jingyi Hu,Qianqian Zhang,Jiali Liu,Siqi Feng

Gastric cancer, a leading cause of cancer-related mortality, has a median survival of just 15 months in advanced stages and currently lacks effective treatment options. Neddylation blockade is a promising therapeutic strategy, yet its clinical application faces challenge with the emergence of drug resistance. Currently, the underlying mechanisms behind the drug resistance are not fully understood. Our study uncovers the link between MLN4924-induced metabolic reprogramming and its antitumor efficacy in gastric cancer cells. We first demonstrated that MLN4924, a neddylation blocker, has multiple effects on gastric cancer cell growth, notably inducing mitochondrial damage. Untargeted metabolomic analysis revealed that MLN4924 enhances glucose utilization in gastric cancer cells in a concentration-dependent manner. Mechanistically, MLN4924 reduces the neddylation of cullin2, thereby inhibiting the degradation of HIF-1α. This leads to the accumulation of HIF-1α, which upregulates GLUT1 levels and facilitates increased glucose uptake. This metabolic adaptation allows gastric cancer cells to maintain their energy supply despite mitochondrial impairment. Based on the increased glucose dependency following neddylation inhibition by MLN4924, we propose a co-targeting strategy with GLUT1 inhibition, which significantly improves therapeutic efficacy in vitro and in vivo models without safety risks. This dual-targeting approach represents a potent new strategy for gastric cancer treatment.

GLUT1 targeting and hypoxia-activating polymer-drug conjugate-based micelle for tumor chemo-thermal therapy

Pengkai Ma,Guijie Wei,Jianhua Chen,Ziqi Jing,Xue Wang,Zhijun Wang

Orientin alleviates ulcerative colitis by regulating ferroptosis and glycolysis via the ROS/HIF-1α/GLUT1 signaling axis

Xin Guo,Bao-Nian Huang,Yu-Han Liu,Yan-Qiu Wang,Huan-Yu Che,Xue-Kun Liu

Ethnopharmacological relevance Crataegus pinnatifida Bunge, a plant used traditionally in herbal medicine for digestive health, is known for its gut-protective properties. Orientin, a natural flavonoid compound abundant in this species, exhibits anti-inflammatory and gut-protective activities. Aim of the study This study examined the therapeutic potential of orientin against ulcerative colitis (UC) and aimed to elucidate its underlying molecular mechanisms. Methods This study established a DSS-triggered UC mouse model. RNA sequencing was carried out to identify key signaling pathways implicated in orientin's therapeutic effects. Disease activity, intestinal barrier integrity, inflammatory responses, ferroptosis, were systematically evaluated. To validate the role of GLUT1 in the pathogenesis of UC, GLUT1-knockdown mice were utilized. Additionally, LPS-stimulated primary intestinal epithelial cells (IECs) were employed to further confirm the protective effects of orientin in vitro. Results RNA sequencing revealed that orientin significantly modulated genes associated with inflammation, ferroptosis, and metabolic pathways. Orientin alleviated DSS-triggered colitis by boosting body weight, preserving colon length, reducing histological damage. GLUT1 deficiency exacerbated intestinal injury, whereas orientin treatment attenuated these effects by regulating the ROS/HIF-1α/GLUT1 signaling axis. Orientin also repressed pro-inflammatory cytokines, neutrophil infiltration, and oxidative stress, while inhibiting the ferroptosis pathway. Moreover, it normalized glycolytic reprogramming by targeting the ROS/HIF-1α/GLUT1 pathway. In vitro studies further confirmed orientin's protective effects on IECs by enhancing barrier function, reducing inflammation, and restoring metabolic homeostasis. Conclusions This study underscores the pivotal role of the ROS/HIF-1α/GLUT1 axis and demonstrates the therapeutic potential of orientin in UC.