检索结果-内蒙古大学图书馆

Yessotoxin induces ER-stress followed by autophagic cell death in glioma cells mediated by mTOR and bnip3

CELLULAR SIGNALLING 2014年第2期26卷 419-432页

作者： Rubiolo, J. A. Lopez-Alonso, H. Martinez, P. Milian, A. Cagide, E. Vieytes, M. R. Vega, F. V. Botana, L. M. USC Fac Vet Dept Farmacol Lugo 27002 Spain Univ Santiago Compostela Fac Vet Dept Genet Lugo 27002 Spain Lab CIFGA SA Lugo 27002 Spain Univ Santiago de Compostela Fac Vet Dept Fisiol Lugo 27002 Spain

Yessotoxin at nanomolar concentrations can induce programmed cell death in different model systems. Paraptosis-like cell death induced by YTX in BC3H1 cells, which are insensitive to several caspase inhibitors, has also been reported. This makes yessotoxin of interest in the search of molecules that target cancer cells vulnerabilities when resistance to apoptosis is observed. To better understand the effect of this molecule at the molecular level on tumor cells, we conducted a transcriptomic analysis using 3 human glioma cell lines with different sensitivities to yessotoxin. We show that the toxin induces a deregulation of the lipid metabolism in glioma cells as a consequence of induction of endoplasmic reticulum stress. The endoplasmic reticulum stress in turn arrests the cell cycle and inhibits the protein synthesis. In the three cell lines used we show that YTX induces autophagy, which is involved in cell death. The sensibility of the cell lines used towards autophagic cell death was related to their doubling time, being the cell line with the lowest proliferation rate the most resistant. The involvement of mTOR and bnip3 in the autophagy induction was also determined. (C) 2013 Elsevier Inc. All rights reserved.

关键词： Yessotoxin Autophagic cell death ER-stress bnip3 mTOR Lipid metabolism

来源：评论

学校读者我要写书评

暂无评论

Neuroprotective role of bnip3 under oxidative stress through autophagy in neuroblastoma cells

引用

MOLECULAR BIOLOGY REPORTS 2014年第9期41卷 5729-5734页

作者： Awan, M. Umer Farooq Hasan, Murtaza Iqbal, Javed Lei, Runhong Lee, Wang Fu Hong, Ma Qing, Hong Deng, Yulin Beijing Inst Technol Sch Life Sci Beijing 100081 Peoples R China

Reactive oxygen species (ROS) are produced due to oxidative stress which has wide range of affiliation with different diseases including cancer, heart failure, diabetes and neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, ischemic and hemorrhagic diseases. This study shows the involvement of bnip3 in the amplification of metabolic pathways related to cellular quality control and cellular self defence mechanism in the form of autophagy. We used conventional methods to induce autophagy by treating the cells with H2O2. MTT assay was performed to observe the cellular viability in stressed condition. MDC staining was carried out for detection of autophagosomes formation which confirmed the autophagy. Furthermore, expression of bnip3 was validated by western blot analysis with LC3 antibody. From these results it is clear that bnip3 plays a key role in defence mechanism by removing the misfolded proteins through autophagy. These results enhance the practical application of bnip3 in neuroblastoma cells and are helpful in reducing the chances of neurodegenerative diseases. Although, the exact mode of action is still unknown but these findings unveil a molecular mechanism for the role of autophagy in cell death and provide insight into complex relationship between ROS and non-apoptotic programmed cell death.

关键词： bnip3 Cell stress Neuroprotective Autophagy Neuroblastoma

来源：评论

学校读者我要写书评

暂无评论

bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling

引用

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2014年第51期111卷 E5537-E5544页

作者： Dhingra, Rimpy Margulets, Victoria Chowdhurya, Subir Roy Thliveris, James Jassal, Davinder Fernyhough, Paul Dorn, Gerald W., II Kirshenbaum, Lorrie A. Univ Manitoba St Boniface Hosp Res Ctr Dept Physiol & Pathophysiol Winnipeg MB R2H 2H6 Canada Univ Manitoba St Boniface Hosp Res Ctr Dept Anat & Cell Sci Winnipeg MB R2H 2H6 Canada Univ Manitoba St Boniface Hosp Res Ctr Fac Hlth Sci Dept Med Winnipeg MB R2H 2H6 Canada Univ Manitoba St Boniface Hosp Res Ctr Inst Cardiovasc Sci Dept Pharmacol & Therapeut Winnipeg MB R2H 2H6 Canada Washington Univ Dept Internal Med Ctr Pharmacogenet Sch Med St Louis MO 63110 USA

Doxorubicin (DOX) is widely used for treating human cancers, but can induce heart failure through an undefined mechanism. Herein we describe a previously unidentified signaling pathway that couples DOX-inducedmitochondrial respiratory chain defects and necrotic cell death to the BH3-only protein Bcl-2-like 19kDa-interacting protein 3 (bnip3). Cellular defects, including vacuolization and disrupted mitochondria, were observed in DOX-treated mice hearts. This coincided with mitochondrial localization of bnip3, increased reactive oxygen species production, loss of mitochondrial membrane potential, mitochondrial permeability transition pore opening, and necrosis. Interestingly, a 3.1-fold decrease in maximal mitochondrial respiration was observed in cardiac mitochondria of mice treated with DOX. In vehicle-treated control cells undergoing normal respiration, the respiratory chain complex IV subunit 1 (COX1) was tightly bound to uncoupling protein 3 (UCP3), but this complex was disrupted in cells treated with DOX. Mitochondrial dysfunction induced by DOX was accompanied by contractile failure and necrotic cell death. Conversely, shRNA directed against bnip3 or a mutant of bnip3 defective for mitochondrial targeting abrogated DOX-induced loss of COX1-UCP3 complexes and respiratory chain defects. Finally, bnip3(-/-)mice treated with DOX displayed relatively normal mitochondrial morphology, respiration, and mortality rates comparable to those of saline-treated WT mice, supporting the idea that bnip3 underlies the cardiotoxic effects of DOX. These findings reveal a new signaling pathway in which DOX-induced mitochondrial respiratory chain defects and necrotic cell death are mutually dependent on and obligatorily linked to bnip3 gene activation. Interventions that antagonize bnip3 may prove beneficial in preventing mitochondrial injury and heart failure in cancer patients undergoing chemotherapy.

关键词： ventricular myocytes mitochondria cell death heart failure bnip3

来源：评论

学校读者我要写书评

暂无评论

Synergism of arsenic trioxide and MG132 in Raji cells attained by targeting bnip3, autophagy, and mitochondria with low doses of valproic acid and vincristine

引用

EUROPEAN JOURNAL OF CANCER 2014年第18期50卷 3243-3261页

作者： Cavaliere, Victoria Lombardo, Tomas Costantino, Susana N. Kornblihtt, Laura Alvarez, Elida M. Blanco, Guillermo A. UBA IDEHU CONICET Lab Inmunotoxicol LaITo Hosp Clin RA-1113 Buenos Aires DF Argentina UBA Fac Farm & Bioquim IDEHU CONICET LIT RA-1113 Buenos Aires DF Argentina UBA Hosp Clin Serv Hematol RA-1113 Buenos Aires DF Argentina

We previously demonstrated that arsenic trioxide (ATO) and proteasome inhibitor MG132 synergistically induced cell death in promonocytic leukaemia cell line U937 but were antagonistic in Burkitt's lymphoma cell line Raji. Here we explore the role of autophagy, expression of bnip3, and mitochondrial mass, in determining whether ATO and MG132 interaction can be shifted from antagonism to synergism in Raji cells. Treatment with ATO + MG132 increased the percentage of cells with collapsed mitochondrial membrane potential (MMP) in U937 cells, but had no effect in Raji cells. Mitochondria were found in cytoplasmic marginal location in U937 cells but at perinuclear location in Raji cells. ATO + MG132 increased mitochondrial mass in U937 cells but decreased it in Raji cells, while autophagy was increased in both cell lines. bnip3 was expressed in U937 cells at cytoplasmic marginal locations and was hardly detected in Raji cells. Histone deacetylase (HDAC) inhibitor valproic acid (VPA) increased expression of bnip3 in Raji cells at perinuclear locations. However antagonism between ATO and MG132 was increased in the presence of low doses of VPA. Addition of vincristine (VCR) blocked autophagy, while VPA + VCR treatment of Raji cells at sub-cytotoxic doses caused bnip3 and mitochondria to redistribute to cytoplasmic peripheral location and increased mitochondrial mass. ATO + MG132 in the presence of subcytotoxic doses of VPA + VCR caused collapse of MMP in Raji cells, while interaction between ATO and MG132 shifted from antagonism to synergism. We conclude that synergism between ATO and MG132 was attained in Raji cells by disruption of the perinuclear mitochondrial cluster, blockage of selective autophagy of mitochondria (mitophagy) by VCR, increased mitochondrial mass, and upregulation of bnip3 by VPA. (C) 2014 Elsevier Ltd. All rights reserved.

关键词： Synergism bnip3 Mitochondria Mitophagy Autophagy Targeted combined therapies Arsenic trioxide MG132 Valproic acid Burkitt's lymphoma

来源：评论

学校读者我要写书评

暂无评论

Induction of autophagy biomarker bnip3 requires a JAK2/STAT3 and MT1-MMP signaling interplay in Concanavalin-A-activated U87 glioblastoma cells

引用

CELLULAR SIGNALLING 2014年第5期26卷 917-924页

作者： Pratt, Jonathan Annabi, Borhane Univ Quebec Lab Oncol Mol Dept Chim Ctr Rech BIOMED Montreal PQ H3C 3P8 Canada

Plant lectins have been considered as possible anti-tumor drugs because of their property to induce autophagic cell death. Given that expression of membrane type-1 matrix metalloproteinase (MT1-MMP) has been found to regulate expression of the autophagy biomarker Bc1-2/adenovirus E1B 19 kDa interacting protein 3 (bnip3), we sought to investigate possible signaling interplay mechanisms between MT1-MMP and bnip3 in Concanavalin-A (ConA) lectin-activated U87 glioblastoma cells. ConA induced acidic vacuole organelle formation as well as bnip3 and MT1-MMP gene and protein expressions, whereas only bnip3 expression was dose-dependently inhibited by the JAK2 tyrosine kinase inhibitor AG490 suggesting a requirement for some STAT-mediated signaling. Gene silencing of MT1-MMP and of STAT3 abrogated ConA-induced STAT3 phosphorylation and bnip3 expression. Correlative analysis shows that STAT3 signaling events occur downstream from MT1-MMP induction. Overexpression of a full length MT1-MMP recombinant protein led to increased bnip3 gene and protein expressions. The cytoplasmic domain of MT1-MMP was also found necessary for transducing STAT3 phosphorylation. Among JAK1, JAK2, JAK3, and TYK2, only JAK2 gene silencing abrogated ConA's effects on MT1-MMP and bnip3 gene and protein expressions. Our study elucidates how MT1-MMP signals autophagy, a process which could contribute to the chemoresistance phenotype in brain cancer cells. (C) 2014 Elsevier Inc. All rights reserved.

关键词： Glioblastoma Concanavalin-A Autophagy JAK/STAT MT1-MMP bnip3

来源：评论

学校读者我要写书评

暂无评论

Copper levels affect targeting of hypoxia-inducible factor 1α to the promoters of hypoxia-regulated genes

引用

JOURNAL OF BIOLOGICAL CHEMISTRY 2018年第38期293卷 14669-14677页

作者： Liu, Xiaojuan Zhang, Wenjing Wu, Zhijuan Yang, Yutao Kang, Y. James Sichuan Univ West China Hosp Regenerat Med Res Ctr Chengdu 610041 Sichuan Peoples R China

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a transcription factor that regulates cellular responses to hypoxia. It controls the expression of both BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (bnip3) and insulin-like growth factor 2 (IGF2). Previous studies have demonstrated that in hypoxia, copper is required for the expression of bnip3 but not for that of IGF2. Here, using ChIP assays, computational analyses, luciferase reporter assays, and real-time quantitative RT-PCR, we sought to better understand how copper regulates the differential target gene selectivity of HIF-1 alpha. Human umbilical vein endothelial cells (HUVECs) were exposed to CoCl2 or hypoxia conditions to increase HIF-1 alpha accumulation. The binding of HIF-1 alpha to hypoxia-responsive element (HRE) sites in the bnip3 or IGF2 gene promoter in high- or low-copper conditions was examined. Our analyses revealed three and two potential HRE sites in the bnip3 and IGF2 promoters, respectively. We identified that HRE (-412/-404) in the bnip3 promoter and HRE (-354/-347) in the IGF2 promoter are the critical binding sites of HIF-1 alpha. Tetraethelenepentamine (TEPA)-mediated reduction in copper concentration did not affect hypoxia- or CoCl2-induced HIF-1 alpha accumulation. However, the copper reduction did suppress the binding of HIF-1 alpha to the HRE (-412/-404) in bnip3 but not the binding of HIF-1 alpha to the HRE (-354/-347) in IGF2. In summary, our findings uncovered the mechanistic basis for differential HIF-1 alpha-mediated regulation of bnip3 and IGF2, indicating that copper regulates target gene selectivity of HIF-1 alpha at least in part by affecting HIF-1 alpha binding to its cognate HRE in the promoters of these two genes.

关键词： hypoxia-inducible factor (HIF) copper transcription target gene chromatin immunoprecipitation (ChIP) gene regulation bnip3 hypoxia responsive element IGF2

来源：评论

学校读者我要写书评

暂无评论

BINP3介导的AIF核转位在水飞蓟宾诱导脑胶质瘤细胞自噬性死亡中的作用及机制

BINP3介导的AIF核转位在水飞蓟宾诱导脑胶质瘤细胞自噬性死亡中的...

引用

作者：王崇丞吉林大学

学位级别：博士

背景:胶质瘤是一种侵袭性的恶性脑肿瘤,参与构成了儿童和成人死亡的主要原因[1]。新诊断的胶质瘤患者的中位生存时间只有14.6个月,即使这些病人已接受了肿瘤外科切除并施以放疗及替莫唑胺(TMZ)化疗[2]。作为烷基化剂TMZ广泛用于治疗原... 详细信息

背景:胶质瘤是一种侵袭性的恶性脑肿瘤,参与构成了儿童和成人死亡的主要原因[1]。新诊断的胶质瘤患者的中位生存时间只有14.6个月,即使这些病人已接受了肿瘤外科切除并施以放疗及替莫唑胺(TMZ)化疗[2]。作为烷基化剂TMZ广泛用于治疗原发性和复发性高级别胶质瘤,但其疗效往往受到肿瘤抗药性的限制[3]。因此,更为有效的胶质瘤治疗新药仍为所需。自噬是一种降解途径,自噬体或自噬溶酶体在细胞质中的形成是其形态学上所具有的特征,细胞内物质或受损的细胞器通过自噬体投递到溶酶体以备清除[4]。自噬在调节细胞命运中起着双重作用。一方面,它保护细胞免受有害的刺激的迫害。另一方面,它会导致细胞死亡,这被称为自噬性死亡[4]。据报道,自噬通过清除受损的线粒体来抑制活性氧(ROS)的积累,从而消除顺铂诱导的肝癌细胞死亡[5]。还发现自噬通过去除氧化应激过程中产生的错误折叠蛋白来保护神经母细胞瘤细胞[6]。因此,自噬对细胞损伤的保护与氧化应激的抑制密切相关。在自噬性死亡的情况下,自噬也伴随着细胞内活性氧的积累,通常认为由活性氧所激活[7,8]。然而,自噬是否能通过增加细胞内ROS或诱导线粒体损伤来促进细胞死亡仍不清楚。水飞蓟素是水飞蓟素中最具生物活性的成分,水飞蓟素是奶蓟(水飞蓟属)的多酚提取物。它被广泛应用于治疗和预防多种肝胆疾病,如酒精性肝病、非酒精性脂肪肝和蘑菇中毒[9,10]。此外,水飞蓟宾不仅对乳腺癌细胞、前列腺癌细胞、胶质瘤细胞等多种肿瘤细胞有较强的抑制作用,而且对TMZ、TRAIL或三氧化二砷等化疗药物也有致敏作用,可预防化疗药物顺铂对肝细胞的损伤。虽然水飞蓟宾可以诱导癌细胞自噬死亡,但水飞蓟宾诱导自噬下游的生化事件尚不清楚。因此,本研究以胶质瘤细胞系及裸鼠移植瘤为研究对象,探讨自噬是否具有促进线粒体损伤的作用及其可能机制。目的:在这项研究里,我们利用多种胶质瘤细胞系以及移植了胶质瘤的裸鼠来调查有bnip3参与的自噬是否促进了水飞蓟宾诱导的胶质瘤细胞死亡。方法:1、通过MTT法检测胶质瘤细胞增殖情况。2、通过LDH释放试验检测胶质瘤细胞死亡率的变化。3、蛋白印迹法(western-blotting)检测胶质瘤细胞及裸鼠组织中相关蛋白含量变化。4、通过流式细胞术检结合JC-1染色检测线粒体膜电位的变化。5、通过荧光显微镜观察JC-1、DCFH-DA、Mitosox染色后胶质瘤细胞形态学上的变化。6、通过激光共聚焦显微镜观察免疫荧光染色后相关蛋白在胶质瘤细胞中的分布情况。7、通过DCFH-DA探针、H2O2检测胶质瘤细胞及裸鼠组织的氧化水平。8、通过构建Stub RFP-Sens GFP-LC3慢病毒转染胶质瘤细胞,观察自噬发生情况。9、通过GSH与半胱氨酸含量的测定,检测胶质瘤细胞及裸鼠组织内还原物质的含量。10、通过Si RNA技术敲除AIF、bnip3和ATG5基因,来研究他们在水飞蓟宾诱导的AIF的核转位或过度线粒体自噬中的作用。11、通过对Balb/c nude裸鼠接种C6胶质瘤细胞,构建肿瘤移植模型,观察体内环境中水飞蓟宾对胶质瘤的抑制作用。结果:1、MTT法检测水飞蓟宾对U87、U251、SHG-44和C6胶质瘤细胞的杀伤作用呈剂量依赖性。Western blotting分析表明,水飞蓟宾诱导ATG5和LC3-II的时间依赖性上调,而自噬底物p62(SQSTM1)的时间依赖性下调。在共聚焦显微镜下观察到Stub RFP-Sens GFP-LC3B慢病毒感染细胞的代表性图像显示,水飞蓟宾诱导自噬体(黄色斑点)和自溶体(紫色斑点)的形成。Western blotting分析表明,3MA可抑制水飞蓟宾诱导的LC3-II的上调和p62的降低。BafilomycinA1逆转了水飞蓟宾诱导的p62降低,但进一步提高了LC3-II水平。LDH释放实验证明,3MA或bafilomycin A1可预防水飞蓟宾诱导的胶质瘤细胞死亡。Western blotting结果表明,Si RNA敲除ATG5可抑制水飞蓟宾诱导的LC3-II的上调和p62的降低。LDH释放实验表明,Si RNA敲除ATG5后,水飞蓟宾诱导的胶质瘤细胞死亡受抑。2、荧光显微镜下JC-1染色的代表性细胞图像显示,水飞蓟宾处理使U87和U251细胞的红色荧光明显减弱。流式细胞术结合JC-1染色证实,水飞蓟宾诱导线粒体膜电位的时间依赖性耗散。在荧光显微镜下,用Mitosox red染色的细胞的代表性图像显示,在水飞蓟宾处理的细胞中显示的红色荧光明显强于对照组。对Mitosox-red显示的红色荧光强度的统计分析表明,水飞蓟宾以时间依赖的方式触发线粒体超氧化物的积累。Western blotting分析表明,水飞蓟宾诱导AIF从线粒体向细胞核的转移具有时间依赖性。共聚焦显微镜结合免疫化学

关键词：胶质瘤水飞蓟宾 bnip3 自噬 AIF

来源：评论

学校读者我要写书评

暂无评论

Dysregulation of Sqstm1, mitophagy, and apoptotic genes in chronic exposure to arsenic and high-fat diet (HFD)

引用

ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH 2018年第34期25卷 34351-34359页

作者： Zeinvand-Lorestani, Marzieh Kalantari, Heibatullah Khodayar, Mohammad Javad Teimoori, Ali Saki, Najmaldin Ahangarpour, Akram Rahim, Fakher Khorsandi, Layasadat Ahvaz Jundishapur Univ Med Sci Toxicol Res Ctr Ahvaz Iran Ahvaz Jundishapur Univ Med Sci Sch Pharm Dept Toxicol Ahvaz Iran Ahvaz Jundishapur Univ Med Sci Sch Med Dept Virol Ahvaz Iran Ahvaz Jundishapur Univ Med Sci Hlth Res Inst Res Ctr Thalassemia & Hemoglobinopathy Ahvaz Iran Ahvaz Jundishapur Univ Med Sci Hlth Res Inst Dept Physiol Diabet Res Ctr Ahvaz Iran Ahvaz Jundishapur Univ Med Sci Cell & Mol Res Ctr Fac Med Ahvaz Iran

Arsenic (As) is a toxic and hazardous metalloid. Unfortunately, its presence in drinking water together with wrong nutritional patterns is associated with an increase in the occurrence of metabolic disorders in young people. Degradation of mitochondria is presented by a specific form of autophagy called mitophagy which is an important landmark leading to apoptosis during lipotoxicity. Lipotoxicity and cellular toxicity due to arsenic intake can lead to changes in mitophagy and apoptosis. The protein derived from SQSTM1 gene, also called p62, plays an important role in energy homeostasis in the liver, and it can contribute to the regulation of autophagic responses given its effect on signaling of mTOR, MAPK, and NF-KB. Consequently, changes in Sqstm1, mitophagy (bnip3), and apoptotic (caspase 3) genes in the livers of NMRI mice were examined with the use of real-time RT-PCR Array followed by exposure to an environmentally relevant and negligible cytotoxic concentration of arsenite (50ppm) in drinking water while being fed with a high-fat diet (HFD) or low-fat diet (LFD) for 20weeks (LFD-As and HFD-As groups). While LFD-As and HFD groups showed a decrease in bnip3 expression, a significant increase was observed in the HFD-As group. P62 gene showed downregulation in LFD-As and HFD groups, and upregeneration was observed in the HFD-As group. Caspase 3 showed increased expression as the key factor associated with apoptotic liver cell death in the three groups, with the highest value in HFD-As group. Overall, the changes observed in the expression of Sqstm1, bnip3, and caspase 3 in this study can be related to the level of liver damage caused by exposure to arsenic and HFD and probably, bnip3 pro-apoptotic protein is associated with an increased cell death due to HFD and As.

关键词： bnip3 Sqstm1 Apoptosis Arsenic HFD

来源：评论

学校读者我要写书评

暂无评论

Silence of lncRNA GAS5 alleviates high glucose toxicity to human renal tubular epithelial HK-2 cells through regulation of miR-27a

引用

Artificial cells, nanomedicine, and biotechnology 2019年第1期47卷 2205-2212页

作者： Lina Lv Dandan Li Fengqun Tian Xia Li Xiulian Yu a Department of Nephrology Jining No.1 People's Hospital Jining China. b Affiliated Jining No.1 People's Hospital of Jining Medical University Jining China. c Department of Endocrinology Jining No.1 People's Hospital Jining China. d Department of Nephrology Jiaxiang County Medicine Hospital Jiaxiang China.

Renal tubular damage caused by persistent high glucose environment has been found to contribute to diabetic nephropathy. This study explored the effects of lncRNA growth arrest-specific 5 (GAS5) on high glucose-stimulated human renal tubular epithelial HK-2 damage, as well as the possible internal molecular mechanism. Viability and apoptosis of HK-2 cells were assessed with the help of CCK-8 assay and Annexin V-FITC/PI staining, respectively. Cell transfection was used to change the expression of GAS5, miR-27a and bnip3. We found that high glucose stimulation suppressed HK-2 cell viability but induced cell apoptosis. The expression of GAS5 was increased in HK-2 cells under high glucose environment. Silence of GAS5 mitigated the high glucose-caused HK-2 cell viability reduction and apoptosis. Overexpression of miR-27a reversed the effects of GAS5 on high glucose-stimulated HK-2 cells. Overexpression of bnip3 aggravated the high glucose-caused HK-2 cell viability reduction, apoptosis and activation of JNK pathway. Knockdown of bnip3 had opposite effects. In conclusion, this research further confirmed the pro-apoptotic roles of GAS5 in renal tubular epithelial cells under high glucose environment. Silence of GAS5 alleviated high glucose toxicity to human renal tubular epithelial HK-2 cells might be via down-regulating miR-27a and bnip3, and then inactivating JNK pathway. Highlights HG suppresses HK-2 cell viability, but promotes cell apoptosis; HG enhances the expression of GAS5 in HK-2 cells; Silence of GAS5 alleviates the HG-caused HK-2 cell toxicity; miR-27a participates in the effects of GAS5 silencing on HG-stimulated HK-2 cells; bnip3 is regulated by miR-27a and related to the HG toxicity to HK-2 cells.

关键词： bnip3 Diabetic nephropathy JNK pathway high glucose lncRNA GAS5 microRNA-27a

来源：评论

学校读者我要写书评

暂无评论

HIF-1α/bnip3信号通路调节的低氧诱导自噬在唾液腺腺样囊性癌中的作用

HIF-1α/BNIP3信号通路调节的低氧诱导自噬在唾液腺腺样囊性癌中...

引用

作者：陈占伟山东大学

学位级别：博士

唾液腺腺样囊性癌(salivary adenoid cystic carcinoma, SACC)是头颈部唾液腺最常见的恶性肿瘤之一,具有嗜神经生长、远期复发率高及易发生全身远处转移等独特的生物学行为。因此,腺样囊性癌曾被描述为头颈部最具破坏性和不可预见性的... 详细信息

唾液腺腺样囊性癌(salivary adenoid cystic carcinoma, SACC)是头颈部唾液腺最常见的恶性肿瘤之一,具有嗜神经生长、远期复发率高及易发生全身远处转移等独特的生物学行为。因此,腺样囊性癌曾被描述为头颈部最具破坏性和不可预见性的肿瘤之一。目前,对于腺样囊性癌尚无行之有效的治疗方案,主要的治疗手段是手术联合放化疗的综合治疗为主,近年来有术后行I125放射性粒子植入作为辅助放疗的报道。虽然5年生存率较高,但其10年甚至更长时间生存率偏低,效果并不满意。因此,进一步了解腺样囊性癌的生物学行为和分子遗传学特征可能找提供新的见解和治疗策略。近年来随着对腺样囊性癌发生发展的分子机制研究的逐步深入,人们发现腺样囊性癌的治疗要想取得突破性进展,需要寻找更具针对性的新目的基因,通过基因转染抑制肿瘤细胞增殖、诱发肿瘤细胞凋亡,是肿瘤基因治疗策略之所在。低氧是实体肿瘤微环境中常见的现象。肿瘤在高速增殖的过程中,血管生成速度显著低于细胞增殖速度,氧供应的速度滞后于细胞对氧的需求,现已有大量研究表明低氧状态与肿瘤的侵袭性、血管再生、提高复发率及放化疗耐受性之间存在复杂的联系。作为氧平衡的重要调节因子,HIF-1是在低氧条件下重要的转录因子。HIF-1是由HIF-1α和HIF-1β两种亚基组成的异源二聚体,HIF-1β是HIF-1的结构性亚基,在细胞内的表达相对稳定；HIF-1α是HIF-1的功能亚基,常氧条件下不断合成,同时不断经泛素-蛋白酶小体途径水解。低氧条件下,HIF-1a降解受阻,在细胞浆内积聚增多,向细胞核内转移,与HIF-1β结合调节靶基因的转录。HIF-1α已经在大多数常见的人类癌症中观察到,如头颈部的恶性肿瘤、卵巢癌和食道癌中,并与不良预后及治疗抵抗相关。Costa等发现HIF-la广泛的在唾液腺腺样囊性癌中表达,而在肿瘤附近正常唾液腺腺体组织鲜有表达。bnip3,即Bcl2/腺病毒ElB 19 kDa相关蛋白3(BCL2/adenovirus ElB 19kDa interacting protein 3),属于促凋亡蛋白,其表达受HIF-1 α依赖的缺氧的调节及其他很多因素的影响。bnip3蛋白主要定位于线粒体外膜,当其被激活后,完全整合入线粒体外膜,通过开放线粒体通透性转运孔(mitochondrial permeability transition pore, MPTP)损伤线粒体功能引起染色质凝聚、DNA分解,最终导致细胞凋亡。近年来,bnip3的异常表达和很多肿瘤的进展、化疗耐药及自噬密切相关。bnip3的表达受到转录因子HIF-la的调控,在低氧诱导细胞自噬凋亡过程中起重要的作用。然而,唾液腺腺样囊性癌中bnip3的表达、其调节的低氧诱导自噬通路及临床病理学行为国内外尚未有文献报道。自噬指的是从粗面内质网上的无核糖体附着区脱落的双层膜包裹的部分胞质和细胞内需要降解的细胞器和蛋白质等形成自噬体,与溶酶体融合后形成自噬溶酶体,进一步降解所包裹的多余蛋白质和亚细胞成分,来实现细胞本身的代谢需要和细胞器的更新,来维持自身的稳定。其整个过程主要分3个阶段：自噬小体的初步形成；自噬体膜的延伸；自噬体与溶酶体融合并降解。氯喹可以通过升高溶酶体内的PH值,进而阻止自噬体与溶酶体结合而抑制自噬。我们的研究团队在之前调查过79名患有头颈部腺样囊性癌的患者,观察自噬相关蛋白微管相关蛋白1轻链-3(microtubule associated protein 1 light chain 3, LC3) 和Beclin1的表达,结果显示二者在腺样囊性癌形成的过程中起重要的作用。近期的研究已经发现低氧状态与诱导自噬之间存在某些联系,然而低氧诱导腺样囊性癌细胞自噬的分子机制尚未完全明确。目的：1、应用二氯化钴在体外构建细胞低氧模型,采用经其处理的腺样囊性癌细胞株ACC-M细胞,模拟其在体内的缺氧环境,观察缺氧条件下低氧相关的HIF-1 α/bnip3通路相关基因、自噬相关基因Beclin1在腺样囊性癌细胞中的表达情况,探讨低氧对唾液腺腺样囊性癌ACC-M细胞增殖和自噬的影响。2、采用二氯化钻模拟低氧条件,研究低氧诱导的自噬对唾液腺腺样囊性癌ACC-M侵袭性的影响,研究氯喹通过抑制低氧诱导的自噬过程而对ACC-M细胞侵袭性的影响。方法：1、应用二氯化钴作为化学性低氧诱导剂,体外构建唾液腺腺样囊性癌ACC-M细胞低氧模型。2、MTT法对ACC-M细胞进行细胞活力测验,以检测二氯化钴对细胞增殖的抑制作用；透射电子显微镜观察自噬体形成；双免疫荧光标记、RT-PCR及Western blot检测低氧相关HIF-1α/bnip3通路相关基因、自噬相关蛋白微管相关蛋白1轻链-3(microtubule associated protei

关键词：腺样囊性癌低氧 HIF-1α bnip3 自噬

来源：评论

学校读者我要写书评

暂无评论

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案：

请选择收藏分类：

通借通还

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：