共查询到20条相似文献,搜索用时 31 毫秒
1.
Kayoko Yoshida Chiyo K. Imamura Kanako Hara Mayumi Mochizuki Yusuke Tanigawara 《Metabolomics : Official journal of the Metabolomic Society》2017,13(8):98
Introduction
Everolimus selectively inhibits mammalian target of rapamycin complex 1 (mTORC1) and exerts an antineoplastic effect. Metabolic disturbance has emerged as a common and unique side effect of everolimus.Objectives
We used targeted metabolomic analysis to investigate the effects of everolimus on the intracellular glycometabolic pathway.Methods
Mouse skeletal muscle cells (C2C12) were exposed to everolimus for 48 h, and changes in intracellular metabolites were determined by capillary electrophoresis time-of-flight mass spectrometry. mRNA abundance, protein expression and activity were measured for enzymes involved in glycometabolism and related pathways.Results
Both extracellular and intracellular glucose levels increased with exposure to everolimus. Most intracellular glycometabolites were decreased by everolimus, including those involved in glycolysis and the pentose phosphate pathway, whereas no changes were observed in the tricarboxylic acid cycle. Everolimus suppressed mRNA expression of enzymes related to glycolysis, downstream of mTOR signaling enzymes and adenosine 5′-monophosphate protein kinases. The activity of key enzymes involved in glycolysis and the pentose phosphate pathway were decreased by everolimus. These results show that everolimus impairs glucose utilization in intracellular metabolism.Conclusions
The present metabolomic analysis indicates that everolimus impairs glucose metabolism in muscle cells by lowering the activities of glycolysis and the pentose phosphate pathway.2.
ObjectivesAPOC1 has been reported to promote tumor progression. Nevertheless, its impact on cell proliferation and glycolysis in gastric cancer (GC) remains to be probed. Hence, this study explored the related impacts and mechanisms.MethodsDLEU1, SMYD2, and APOC1 expression was detected in GC cells. Afterward, ectopic expression and knockdown experiments were conducted in GC cells, followed by measurement of cell proliferation, glucose uptake capability, lactic acid production, ATP content, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), and GLUT1, HK2, and LDHA expression. In addition, interactions between DLEU1 and SMYD2 were analyzed with RIP and RNA pull down assays, and the binding of SMYD2 to APOC1 promoter and the methylation modification of SMYD2 in H3K4me3 were assessed with a ChIP assay. The ectopic tumor formation experiment in nude mice was conducted for in vivo validation.ResultsDLEU1, SMYD2, and APOC1 were highly expressed in GC cells. The downregulation of DLEU1 or APOC1 inhibited glucose uptake capability, lactic acid production, ECAR, the expression of GLUT1, HK2, and LDHA, ATP contents, and proliferation but augmented OCR in GC cells, which was also verified in animal experiments. Mechanistically, DLEU1 interacted with SMYD2 and recruited SMYD2 to APOC1 promoter to promote H3K4me3 modification, thus facilitating APOC1 expression. Furthermore, the effects of DLEU1 silencing on GC cell proliferation and glycolysis were negated by overexpressing SMYD2 or APOC1.ConclusionLncRNA DLEU1 recruited SMYD2 to upregulate APOC1 expression, thus boosting GC cell proliferation and glycolysis. 相似文献
3.
Xiaojing Tong Peng Mu Yuhua Zhang Jiao Zhao Xiaobin Wang 《Journal of cellular physiology》2020,235(11):8236-8245
Tripartite motif containing 59 (TRIM59) functions as an oncoprotein in various human cancers including ovarian cancer. In this study, we found that TRIM59 gene amplification was prevalent in ovarian cancer tissues, and its amplification was significantly correlated with poorer overall survival. Moreover, knockdown of TRIM59 in SKOV3 and OVCAR3 cells, which had relatively high level of TRIM59, suppressed glucose uptake and lactate production. TRIM59 knockdown also decreased the expression of c-Myc and lactate dehydrogenase A, and the phosphorylation of extracellular signal-regulated kinase (ERK). TRIM59 overexpression in A2780 cells, which expressed low level of TRIM59, showed reverse effects. Notably, treatment with an ERK inhibitor (PD98059) completely abolished the oncogenic effects of TRIM59 overexpression. Interestingly, TRIM59 increased the ubiquitination of MAP kinase phosphatase 3 (MKP3), which may dephosphorylate and inactivate ERK. Ectopic expression of MKP3 inhibited the promoting effects of TRIM59 on glycolysis and the phosphorylation of ERK. TRIM59 protein expression was negatively correlated with MKP3 protein expression in ovarian cancer tissues. Finally, TRIM59 amplification potently affected the anticancer effect of 3-bromopyruvate, an inhibitor of glycolysis, in ovarian cancer cells and patient-derived xenograft. In conclusion, these results suggest that TRIM59 may regulate glycolysis in ovarian cancer via the MKP3/ERK pathway. 相似文献
4.
Eva Gottfried Sven A. Lang Kathrin Renner Anja Bosserhoff Wolfram Gronwald Michael Rehli Sabine Einhell Isabel Gedig Katrin Singer Anton Seilbeck Andreas Mackensen Oliver Grauer Peter Hau Katja Dettmer Reinhard Andreesen Peter J. Oefner Marina Kreutz 《PloS one》2013,8(7)
Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor α-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies. 相似文献
5.
6.
The mTOR inhibitor everolimus (RAD001, Afinitor) is an orally active anticancer agent. Everolimus demonstrates growth-inhibitory activity against a broad range of tumor cell histotypes in vitro and has the capacity to retard tumor growth in preclinical tumor models in vivo through mechanisms directed against both the tumor cell and the solid tumor stroma components. These properties have rendered it to be a clinically active drug, with subsequent registration in renal cell carcinoma (Motzer et al. [2008]. Lancet 372, 449–456) as well as showing strong potential as a combination partner (André F et al. [2008]. J Clin Oncol 26. Abstract 1003). Although everolimus has a high specificity for its molecular target, the ubiquitous nature of mTOR and the multifactorial influence that mTOR signaling has on cell physiology have made studies difficult on the identification and validation of a biomarker set to predict and monitor drug sensitivity for clinical use. In this review, a summary of the preclinical and clinical data relevant to biomarker development for everolimus is presented, and the advantages and problems of current biomarkers are reviewed. In addition, alternative approaches to biomarker development are proposed on the basis of examples of a combination of markers and functional noninvasive imaging. In particular, we show how basal levels of pAKT and pS6 together could, in principle, be used to stratify patients for likely response to an mTOR inhibitor. 相似文献
7.
Faggiano A Ramundo V Dicitore A Castiglioni S Borghi MO Severino R Ferolla P Crinò L Abbruzzese A Sperlongano P Caraglia M Ferone D Hofland L Colao A Vitale G 《Journal of cellular and molecular medicine》2012,16(7):1563-1572
Everolimus, an mTOR inhibitor, which has been demonstrated to induce anti-tumour effects in different types of neuroendocrine tumours, has never been evaluated in patients with medullary thyroid cancer (MTC). The aim of this study was to evaluate the in vitro and in vivo effects of everolimus in combination with octreotide in MTC. Two patients with progressive metastatic MTC and high calcitonin levels were treated with everolimus 5-10 mg/day. Both patients were under treatment with octreotide LAR at the study entry. An in vitro study was also performed to assess everolimus effects on MTC cell lines (TT and MZ-CRC-1 cells). A tumour response was observed in both patients. Serum calcitonin decreased by 86% in patient 1 and by 42% in patient 2. In TT and MZ-CRC-1 cells, everolimus induced a significant dose-dependent inhibition in cell proliferation. This effect seems to be related to a cell cycle arrest in G(0) /G(1) phase in both cell lines and to the induction of cellular senescence in TT cells. Everolimus in combination with octreotide may be active as anti-tumour therapy in patients with progressive metastatic MTC, suggesting to further evaluate this agent in MTC patients in a large prospective study. 相似文献
8.
9.
Jing Yang Xing Zhang Jiacheng Cao Penghui Xu Zetian Chen Sen Wang Bowen Li Lu Zhang Li Xie Lang Fang Zekuan Xu 《Cell death & disease》2021,12(10)
Gastric cancer remains the third leading cause of cancer-related mortality worldwide. Emerging evidence has shown that circular RNAs (circRNAs) play a critical regulatory role in the occurrence and development of various cancers through sponging miRNAs or acting as RNA-binding protein (RBP) sponges. We found that circUBE2Q2 was significantly upregulated in GC tissues and cell lines. Knockdown of circUBE2Q2 inhibited proliferation, migration, invasion, and glycolysis, and increased autophagy in vitro. In addition, knockdown of circUBE2Q2 inhibited GC tumorigenicity and metastasis potential in vivo. A series of experiments were performed to confirm that circUBE2Q2 regulates GC progression via the circUBE2Q2-miR-370-3p-STAT3 axis and promotes tumor metastasis through exosomal communication. Further in vivo experiments confirmed that, combination treatment of circUBE2Q2 knocking down and STAT3 inhibitor has synergistic effects on the gastric cancer growth inhibition, which provides a possibility to enhance the sensitivity of targeted drugs to gastric cancer through targeting circUBE2Q2. Our findings revealed that circUBE2Q2 may serve as a new proliferation-promoting factor and prognostic marker in gastric cancer.Subject terms: Gastric cancer, Gastric cancer 相似文献
10.
Sixuan?Qian Jianyong?Li Ming?Hong Yu?Zhu Huihui?Zhao Yue?Xie Jiayu?Huang Yun?Lian Yanru?Li Shuai?Wang Jianping?Mao Yaoyu?Chen
Background
Cancer cells show increased glycolysis and take advantage of this metabolic pathway to generate ATP. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits aerobic glycolysis and protects tumor cells from intracellular reactive oxygen species (ROS)-associated apoptosis. However, the function of TIGAR in glycolysis and survival of acute myeloid leukemia cells remains unclear.Methods
We analyzed TIGAR expression in cytogenetically normal (CN-) AML patients and the correlations with clinical and biological parameters. In vivo and in vitro, we tested whether glycolysis may induce TIGAR expression and evaluated the combination effect of glycolysis inhibitor and TIGAR knockdown on human leukemia cell proliferation.Results
High TIGAR expression was an independent predictor of poor survival and high incidence of relapse in adult patients with CN-AML. TIGAR also showed high expression in multiple human leukemia cell lines and knockdown of TIGAR activated glycolysis through PFKFB3 upregulation in human leukemia cells. Knockdown of TIGAR inhibited the proliferation of human leukemia cells and sensitized leukemia cells to glycolysis inhibitor both in vitro and in vivo. Furthermore, TIGAR knockdown in combination with glycolysis inhibitor 2-DG led leukemia cells to apoptosis. In addition, the p53 activator Nutlin-3α showed a significant combinational effect with TIGAR knockdown in leukemia cells. However, TIGAR expression and its anti-apoptotic effects were uncoupled from overexpression of exogenous p53 in leukemia cells.Conclusions
TIGAR might be a predictor of poor survival and high incidence of relapse in AML patients, and the combination of TIGAR inhibitors with anti-glycolytic agents may be novel therapies for the future clinical use in AML patients.11.
Ben Liu Meng Zhou Xiangchun Li Xining Zhang Qinghua Wang Luyang Liu Meng Yang Da Yang Yan Guo Qiang Zhang Hong Zheng Qiong Wang Lian Li Xinlei Chu Wei Wang Haixin Li Fengju Song Yuan Pan Wei Zhang Kexin Chen 《Cell death & disease》2021,12(5)
There is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.Subject terms: Tumour biomarkers, Translational research 相似文献
12.
Qian Mi Yuru Ma Xiangqian Gao Ran Liu Pengxing Liu Yi Mi 《Journal of biomolecular structure & dynamics》2016,34(11):2339-2350
Malignant neoplasms exhibit an elevated rate of glycolysis over normal cells. To target the Warburg effect, we designed a new series of 2-deoxyglucose (2-DG) conjugated platinum (II) complexes for glucose transporter 1 (GLUT1)-mediated anticancer drug delivery. The potential GLUT1 transportability of the complexes was investigated through a comparative molecular docking analysis utilizing the latest GLUT1 protein crystal structure. The key binding site for 2-DG as GLUT1’s substrate was identified with molecular dynamics simulation, and the docking study demonstrated that the 2-DG conjugated platinum (II) complexes can be recognized by the same binding site as potential GLUT1 substrate. The conjugates were synthesized and evaluated for in vitro cytotoxicity study with seven human cancer cell lines. The results of this study revealed that 2-DG conjugated platinum (II) complexes are GLUT1 transportable substrates and exhibit improved cytotoxicities in cancer cell lines that over express GLUT1 when compared to the clinical drug, Oxaliplatin. The correlation between GLUT1 expression and antitumor effects are also confirmed. The study provides fundamental information supporting the potential of the 2-DG conjugated platinum (II) complexes as lead compounds for further pharmaceutical R&D. 相似文献
13.
Masayuki Yasugi Nagio Takigawa Nobuaki Ochi Kadoaki Ohashi Daijiro Harada Takashi Ninomiya Toshi Murakami Yoshihiro Honda Eiki Ichihara Mitsune Tanimoto Katsuyuki Kiura 《Experimental cell research》2014
Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1 mm in the everolimus-treated and control groups were 1.9±0.9 and 9.4±3.2 (t-test, p<0.001), respectively. pS6 was suppressed during everolimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation. 相似文献
14.
15.
Weihong Xu Yanan Lai Yunqi Pan Meiyu Tan Yanyun Ma Huiming Sheng Jiucun Wang 《Cell death & disease》2022,13(8)
Gastric cancer (GC) is a malignancy with poor prognosis. NDUFA4 is reported to correlate with the progression of GC. However, its underlying mechanism in GC is unknown. Our study was to reveal the pathogenic mechanism of NDUFA4 in GC. NDUFA4 expression was explored in single-cell and bulk RNA-seq data as well as GC tissue microarray. Mitochondrial respiration and glycolysis were estimated by oxygen consumption rate and extracellular acidification rate, respectively. The interaction between NDUFA4 and METTL3 was validated by RNA immunoprecipitation. Flow cytometry was used to estimate cell cycle, apoptosis and mitochondrial activities. NDUFA4 was highly expressed in GC and its high expression indicated a poor prognosis. The knockdown of NDUFA4 could reduce cell proliferation and inhibit tumor growth. Meanwhile, NDUFA4 could promote glycolytic and oxidative metabolism in GC cells, whereas the inhibition of glycolysis suppressed the proliferation and tumor growth of GC. Besides, NDUFA4 inhibited ROS level and promoted MMP level in GC cells, whereas the inhibition of mitochondrial fission could reverse NDUFA4-induced glycolytic and oxidative metabolism and tumor growth of GC. Additionally, METTL3 could increase the m6A level of NDUFA4 mRNA via the m6A reader IGF2BP1 to promote NDUFA4 expression in GC cells. Our study revealed that NDUFA4 was increased by m6A methylation and could promote GC development via enhancing cell glycolysis and mitochondrial fission. NDUFA4 was a potential target for GC treatment.Subject terms: Gastric cancer, Cancer metabolism 相似文献
16.
Xichao Sun Cheng Xue Yiting Jin Chao Bian Na Zhou Shengming Sun 《The Journal of biological chemistry》2023,299(1)
Crustaceans have an open vascular system in which hemocytes freely circulate in hemolymph. Hemocytes are rich in hemocyanin, a specific oxygen-transport protein in crustaceans; therefore, understanding the response of hemocytes to hypoxia is crucial. Although hemocytes take up glucose during hypoxia, the molecular mechanism of glucose uptake in crustaceans remains unclear. Herein, we identified two highly conserved glucose transporters (GLUT1 and GLUT2) in Macrobrachium nipponense (oriental river prawn) and analyzed their tissue-specific expression patterns. Our immunofluorescence assays showed that GLUT1 and GLUT2 are located on the cell membrane, with a strong GLUT1 signal in primary hemocytes under hypoxia. We found that during acute hypoxia, hypoxia-inducible factor-1α–related metabolic alterations result in decreased mitochondrial cytochrome c oxidase activity, implying a classic glycolytic mechanism. As a proof of concept, we replicated these findings in insect S2 cells. Acute hypoxia significantly induced hypoxia-inducible factor-1α, GLUT1, and pyruvate dehydrogenase kinase isozyme 1 expression in primary hemocytes, and hypoxia-induced increases in glucose uptake and lactate secretion were observed. GLUT1 knockdown induced intracellular reactive oxygen species generation and apoptosis in vitro and in vivo, resulting in increased prawn mortality and more apoptotic cells in their brains, implying a vital function of GLUT1 in hypoxia adaptation. Taken together, our results suggest a close relationship between hypoxia-mediated glycolysis and GLUT1 in hemocytes. These results demonstrated that in crustaceans, adaptation to hypoxia involves glucose metabolic plasticity. 相似文献
17.
Myoung Sook Kim Xiaofei Chang Cynthia LeBron Jatin K. Nagpal Juna Lee Yiping Huang Keishi Yamashita Barry Trink Edward A. Ratovitski David Sidransky 《PloS one》2010,5(2)
Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation. Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/β-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction. The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of β-catenin expression, and was decreased by the treatment of 2-Deoxyglucose, a glycolytic inhibitor, or API-2, an Akt inhibitor. Loss of NEFH activates the Akt/β-catenin pathway and increases glycolysis and mitochondrial dysfunction. Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways. 相似文献
18.
Zhongyin Yang Chen Li Chao Yan Jianfang Li Min Yan Bingya Liu Zhenggang Zhu Yingli Wu Qinlong Gu 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):181-192
The kinesin family member 14 (KIF14) is a potential oncogene and is involved in the metastasis of various cancers. Nevertheless, its function in gastric cancer (GC) remains poorly defined. The expression of KIF14 was examined in GC cell lines and a clinical cohort of GC specimens by qPCR, western blotting and immunohistochemistry (IHC) staining. The relationship between KIF14 expression and the clinicopathological features was analyzed. The effect of KIF14 on cell proliferation, colony formation, invasion and migration were investigated in vitro and in vivo. The expression of KIF14 was significantly increased in the GC tissues and cell lines. High KIF14 expression was associated with tumor stage, tumor-node-metastasis (TNM) stage and metastasis. KIF14 was an independent prognostic factor for the overall survival of GC, and a higher expression of KIF14 predicted a poorer survival. KIF14 silencing resulted in attenuated proliferation, invasion and migration in human gastric cancer cells, whereas KIF14 ectopic expression facilitated these biological abilities. Notably, the depressed expression of KIF14 inhibited Akt phosphorylation, while overexpressed KIF14 augmented Akt phosphorylation. Additionally, there was a significant correlation between the expression of KIF14 and p?Akt in GC tissues. Importantly, the proliferation, invasion and migration of the GC cells, which was promoted by KIF14 overexpression, was abolished by the Akt inhibitor MK-2206, while Akt overexpression greatly rescued the effects induced by KIF14 knockdown. Our findings are the first to demonstrate that KIF14 is overexpressed in GC, is correlated with poor prognosis and plays a crucial role in the progression and metastasis of GC. 相似文献
19.
Jonathan H Fox Teal Connor Vanita Chopra Kate Dorsey Jibrin A Kama Dorothee Bleckmann Claudia Betschart Daniel Hoyer Stefan Frentzel Marian DiFiglia Paolo Paganetti Steven M Hersch 《Molecular neurodegeneration》2010,5(1):26