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去甲基化药物逆转结肠癌细胞株sw620/L-OHP耐药性的作用及机理研究

四川大学学报（医学版） 2010年第6期41卷 975-979页

作者：邓茜李志平黄春梅刘桢钟仁明李爱军毕锋唐秋琳四川大学华西医院肿瘤中心腹部肿瘤科成都610041 四川大学华西医院肿瘤放射治疗中心成都610041 四川大学华西医院信号转导与分子靶向治疗实验室成都610041

目的探讨甲基转移酶抑制剂5-氮杂-2’-脱氧胞苷(5-aza-dC)对结肠癌奥沙利铂(L-OHP)耐药细胞株sw620/L-OHP耐药性的逆转作用及其作用机制。方法应用5-aza-dC作用于结肠癌细胞sw620与其L-OHP耐药细胞sw620/L-OHP,CCK-8法检测其逆转耐药作... 详细信息

目的探讨甲基转移酶抑制剂5-氮杂-2’-脱氧胞苷(5-aza-dC)对结肠癌奥沙利铂(L-OHP)耐药细胞株sw620/L-OHP耐药性的逆转作用及其作用机制。方法应用5-aza-dC作用于结肠癌细胞sw620与其L-OHP耐药细胞sw620/L-OHP,CCK-8法检测其逆转耐药作用;应用Westernblot检测5-aza-dC使用前后sw620/L-OHP细胞中bnip3基因及耐药基因编码的P糖蛋白(P-GP)、多药耐药相关蛋白(MRP)表达水平的变化;应用同位素微量示踪法检测5-aza-dC使用前后sw620/L-OHP细胞中甲基转移酶(DNMT)的活性。结果 1.4μmol/L5-aza-dC能使L-OHP对sw620/L-OHP细胞IC50由(0.335±0.043)μg/mL降到(0.069±0.023)μg/mL,逆转耐药倍数为8.26倍(P<0.001);5-aza-dC能使sw620/L-OHP细胞中P-GP、MRP蛋白表达增加(P<0.05),但增加程度与5-aza-dC剂量变化无关(P>0.05);另外5-aza-dC还能使表达低下的bnip3蛋白重新表达,且其表达水平随5-aza-dC浓度的增加而增加(P<0.001);5-aza-dC能够降低sw620/L-OHP细胞中DNMT的活性(P<0.001)。结论 5-aza-dC通过降低DNMT活性来上调bnip3的表达,并协同某种机制抑制P-GP、MRP的进一步表达,从而逆转sw620/L-OHP细胞耐药性。

关键词： bnip3 P糖蛋白多药耐药相关蛋白甲基转移酶5-氮杂-2’-脱氧胞苷逆转耐药

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Mechanical unloading of the failing heart exposes the dynamic nature of autophagy

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AUTOPHAGY 2010年第1期6卷 155-156页

作者： Wellnitz, Kari Taegtmeyer, Heinrich Univ Texas Houston Sch Med Dept Med Div Cardiol Houston TX 77030 USA

Mechanical unloading with a left-ventricular assist device decreases the energy demand of the failing human heart. Here, we describe our recent work showing that markers and mediators of autophagy in the failing heart are down-regulated by mechanical unloading. These observations are consistent with the concept that autophagy may be an adaptive mechanism to secure survival of the failing heart muscle cell.

关键词： autophagy heart failure left ventricular assist device bnip3 caspase3/procaspase3

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Autofágie v srdci

Autofágie v srdci

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作者： Šprláková, Katarína Charles University of Prague

Currently, it is growing evidence that autophagy is involved in the prevention of various diseases, which of course also includes heart diseases. This thesis is therefore aimed at clarifying the role of autophagy in the heart, especially during ischemia and subsequent reperfusion. Autophagy is a physiological cellular process by which the cell maintains homeostasis by eliminating long-lived proteins and damaged organelles. The role of autophagy during ischemia/reperfusion in the heart is complex. Predominantly it functions as a pro-survival pathway, because it protects the heart from ischemia or hypoxia. However, when triggered over, which happens during reperfusion, it may lead to cell death. In the heart autophagy is activated in response to various stimuli, such as decrease in ATP and subsequent activation of AMPK, protein bnip3, reactive oxygen and nitrogen species, the opening of mitochondrial permeability transition pore, endoplasmic reticulum stress or unfolded protein response.

关键词： autophagy mTOR Beclin1 hypoxia bnip3 unfolded protein response ischemia reperfusion cardioprotection

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Autophagy inhibition induces atrophy and myopathy in adult skeletal muscles

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AUTOPHAGY 2010年第2期6卷 307-309页

作者： Masiero, Eva Sandri, Marco Univ Padua Dept Biomed Sci Padua Italy VIMM Padua Italy Dulbecco Telethon Inst Padua Italy

Autophagy is required for cellular survival and for the clearance of damaged proteins and altered organelles. Excessive autophagy activation contributes to muscle loss in different catabolic conditions. However, the function of basal autophagy for homeostasis of skeletal muscle was unknown. To clarify this issue we have generated conditional and inducible knockout mice for the critical gene Atg7, to block autophagy specifically in skeletal muscle. Atg7 null muscles reveal an unexpected phenotype which is characterized by muscle atrophy, weakness and features of myofiber degeneration. Morphological, biochemical and molecular analyses of our autophagy knockout mice show the presence of protein aggregates, abnormal mitochondria, accumulation of membrane bodies, sarcoplasmic reticulum distension, vacuolization, oxidative stress and apoptosis. Moreover, autophagy inhibition does not protect skeletal muscles from atrophy during denervation and fasting, but instead promotes greater muscle loss. In conclusion, autophagy plays a critical role for myofiber maintenance and its activation is crucial to avoid accumulation of toxic proteins and dysfunctional organelles that, in the end, would lead to atrophy and weakness.

关键词： skeletal muscle mitochondria protein aggregate FoxO Atrophy myopathy bnip3 autophagy Muscle wasting dystrophy

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bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak

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BIOCHEMICAL JOURNAL 2007年第Pt 3期405卷 407-415页

作者： Kubl, Dieter A. Ycaza, John E. Gustafsson, Asa B. Scripps Res Inst Dept Mol & Expt Med La Jolla CA 92037 USA

bnip3 is a pro-apoptotic member of the Bcl-2 family that is down-regulated in pancreatic cancers, which correlates with resistance to chemotherapy and a worsened prognosis. In contrast, bnip3 is up-regulated in heart failure and contributes to loss of myocardial cells during I/R (ischaemia/reperfusion). bnip3 exerts its action at the mitochondria, but the mechanism by which bnip3 mediates mitochondrial dysfunction is not clear. In the present study, we have identified Bax and Bak as downstream effectors of bnip3-mediated mitochondrial dysfunction. bnip3 plays a role in hypoxia-mediated cell death, but MEFs (mouse embryonic fibroblasts) derived from mice deficient in Bax and Bak were completely resistant to hypoxia even with substantial up-regulation of bnip3. These cells were also resistant to bnip3 overexpression, but re-expression of Bax or Bak restored susceptibility to bnip3, suggesting that bnip3 can act via either Bax or Bak. In contrast, bnip3 overexpression in wild-type MEFs induced mitochondrial dysfunction with loss of membrane potential and release of cytochrome c. Cell death by bnip3 was reduced in the presence of mPTP (mitochondrial permeability transition pore) inhibitors, but did not prevent bnip3-mediated activation of Bax or Bak. Moreover, overexpression of bnip3 Delta TM, a dominant-negative form of bnip3, reduced translocation of GFP (green fluorescent protein)-Bax to mitochondria during sI/R (simulated I/R) in HL-1 myocytes. Similarly, down-regulation of bnip3 using RNA interference decreased activation of Bax in response to sI/R in HL-1 myocytes. These results suggest that bnip3 mediates mitochondrial dysfunction through activation of Bax or Bak which is independent of mPTP opening.

关键词： apoptosis Bak Bax bnip3 ischaemia/reperfusion mitochondrial permeability transition pore

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bnip3 expression in follicular lymphoma

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HISTOPATHOLOGY 2007年第5期50卷 555-560页

作者： Sington, J. Giatromanolaki, A. Campo, L. Turley, H. Pezzella, F. Gatter, K. C. Univ Oxford John Radcliffe Hosp Nuffield Dept Clin Lab Sci Oxford OX3 9DU England

Aims To investigate the role of bnip3, a 19-kDa interacting protein of the Bcl-2 family, alongside Bcl-2 in follicular lymphoma in comparison with reactive lymphoid hyperplasia. The results were compared with those from p53 and caspase-3 (apoptotic markers) and Ki67 (proliferation marker). Methods and results Immunohistochemistry using monoclonal antibodies showed bnip3 to be strongly expressed in most follicular lymphomas but to be weak to negative in all of the reactive cases. There was also an inverse relationship with Bcl-2 expression. There was no correlation of bnip3 immunoreactivity with proliferation and caspase and p53 were virtually negative in all follicular lymphomas and reactive lymphoid cases. Conclusions bnip3 is strongly expressed in most follicular lymphomas, especially those that are Bcl-2 negative. bnip3 may serve as a marker of more aggressive behaviour in follicular lymphoma and be useful diagnostically in the distinction from reactive lymphadenitis.

关键词： Bcl-2 bnip3 follicular lymphoma reactive lymphadenopathy

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Selective silencing of the hypoxia-inducible factor 1 target gene bnip3 by histone deacetylation and methylation in colorectal cancer

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ONCOGENE 2007年第1期26卷 132-141页

作者： Bacon, A. L. Fox, S. Turley, H. Harris, A. L. Univ Oxford John Radcliffe Hosp Mol Oncol Lab Weatherall Inst Mol MedCanc Res UK Oxford OX3 9DU England

Hypoxia, via the hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2), upregulates many genes involved in cell survival. However, proapoptotic pathways are also induced. BCL-2/adenovirus E1B-19kDa-interacting protein 3 (bnip3) represents a paradigm of a cell death protein that is hypoxically upregulated via HIF-1 in most cancers. We found that in contrast to many other cell types, 6/8 colorectal cancer (CRC) cell lines show little hypoxic induction of bnip3 despite an intact HIF signalling system. Colorectal tumour tissue also loses bnip3 expression relative to matched normal samples. Downregulation of hypoxic bnip3 in CRC cells was independent of the expression of other BCL-2 family members, or bnip3L. That bnip3 plays a functional role in hypoxic survival in CRC cells was demonstrated by the fact that CRC cell lines that do not upregulate bnip3 or have been treated with bnip3 RNA interference were insensitive to hypoxia-induced cell death. Promoter methylation and histone deacetylation were shown to silence bnip3 in these CRC cell lines. Of significance, hypoxic induction of bnip3 was restored in 4/6 cell lines by trichostatin-A treatment alone. These data suggest that bnip3 plays an important role in hypoxic cell death and epigenetic mechanisms selectively silence its expression in CRC.

关键词： bnip3 hypoxia histone deacetylation HIF silencing

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Mutational and expressional analysis of bnip3, a pro-apoptotic Bcl-2 member, in gastric carcinomas

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APMIS 2007年第11期115卷 1274-1280页

作者： Lee, Sung Hak Jeong, Eun Goo Yoo, Nam Jin Lee, Sug Hyung Catholic Univ Korea Coll Med Dept Pathol Seoul 137701 South Korea

Cell death deregulation is a hallmark of human cancers. bnip3 was initially identified as a proapoptotic member of the Bcl-2 family and plays an important role in apoptosis, necrosis and autophagy. The aim of this study was to see whether alterations of bnip3 protein expression and somatic mutation of the bnip3 gene are characteristics of human cancers. We analyzed the expression of bnip3 protein in 60 gastric adenocarcinomas by immunohistochemistry. In addition, we analyzed bnip3 mutation in the DNA sequences encoding BH3 (Bcl-2 homology3) and TM (transmembrane) domains that are important in the cell death function of bnip3 by single-strand conformation polymorphism (SSCP) in 48 colorectal, 48 gastric, and 48 breast carcinomas, and 48 acute leukemias. By immunohistochemistry, bnip3 protein was detected in 40 of the 60 carcinomas (67%). Both early and advanced gastric carcinomas expressed bnip3. There was no significant association between bnip3 expression and clinicopathologic characteristics, including invasion, metastasis and stage. In contrast to the cancer cells, epithelial cells in normal gastric mucosa showed no or weak expression of bnip3. Mutational analysis revealed bnip3 mutation in neither the BH3 nor the TM domain, suggesting that bnip3 mutation in these domains is not a direct target of inactivation in gastric, colorectal and breast carcinomas, and acute leukemias. Increased expression of bnip3 in the malignant gastric epithelial cells compared to the normal mucosal epithelial cells suggests that bnip3 expression might play a role in gastric carcinoma development.

关键词： bnip3 expression mutation gastric carcinoma apoptosis

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脑缺血后海马CA1区caspase非依赖性凋亡相关蛋白表达水平的改变以及亚细胞定位

脑缺血后海马CA1区caspase非依赖性凋亡相关蛋白表达水平的改变以...

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作者：张明海南方医科大学

学位级别：硕士

脑血管病发病率高,严重危害人类健康。脑中风是目前最常见的危及人类生命的神经系统疾病,是当今第二大死亡原因及首位致残原因。脑缺血损伤所致的神经元大量死亡是导致中风后神经功能丧失的主要原因,而目前仍未阐明缺血性脑损伤的机制,... 详细信息

脑血管病发病率高,严重危害人类健康。脑中风是目前最常见的危及人类生命的神经系统疾病,是当今第二大死亡原因及首位致残原因。脑缺血损伤所致的神经元大量死亡是导致中风后神经功能丧失的主要原因,而目前仍未阐明缺血性脑损伤的机制,临床上也缺乏有效的治疗手段。因此,研究缺血性神经元死亡机制,探索新的治疗靶点将具有重要意义。脑中风可引起缺血中心区(缺血坏死区)神经元的急性损伤,以及缺血半暗区(缺血坏死区周围有一较病灶中心密度稍低的区域,称病灶周围区或半暗区)神经元的继发性损伤,即迟发性神经元死亡。迟发性神经元死亡的发生机制主要为凋亡,凋亡是一种高度调节的程序性细胞死亡过程,以往的研究表明,caspase(天冬氨酸特异性半胱氨酸蛋白酶)依赖性机制在这一过程中起重要作用,但最近有越来越多的研究表明casepase非依赖性机制也参与了迟发性神经元死亡。虽然目前对caspase非依赖性细胞凋亡的调节机制尚不明确,但已经发现了一些与caspase非依赖性细胞凋亡相关的分子,如Bcl-2与腺病毒E1B-19K相互作用蛋白3(bnip3),凋亡诱导因子(AIF),核酸内切酶G (EndoG)等。我们实验室的前期工作已经发现,在原代培养的海马神经元氧葡萄糖剥夺/复氧(OGD/R)模型中,bnip3的表达升高并且插入到线粒体上,继而诱导线粒体内的AIF由线粒体释放,转位到细胞核引起细胞损伤。但bnip3是否参与大鼠全脑缺血/再灌注损伤中海马神经元的死亡以及是否发生AIF的核转位目前还不清楚。 bnip3是一种促凋亡蛋白,属于Bcl-2家族促细胞凋亡亚家族中的BH3-only亚家族,研究表明bnip3参与了包括上皮细胞,心肌细胞,神经胶质细胞,神经元等多种细胞的死亡过程。Bcl-2家族众多成员参与了细胞损伤过程。其中bnip3是BH3-Only亚家族中对缺氧最敏感的促凋亡蛋白。Bcl-2家族大多数促凋亡成员均含有为其线粒体定位及诱导细胞死亡所需的BH3结构域和C末端跨膜结构域。bnip3也含有BH3结构域,但该结构域既不是bnip3与其他Bcl-2家族成员形成异二聚体所必须的,也不是bnip3诱导细胞死亡所必需的,这表明bnip3不同于其他Bcl-2家族蛋白。研究进一步表明,内源性bnip3与线粒体疏松结合,当受到凋亡信号刺激时,bnip3靠它的跨膜结构域插入线粒体外膜,引起线粒体通透性转换孔(permeability transition pores, PTP)开放,线粒体膜内外电化学梯度降低,氧自由基产生增多,线粒体功能失调,进而导致细胞死亡。bnip3介导的细胞死亡不依赖于细胞色素C的释放以及Apaf-1, caspase的激活,以早期质膜以及线粒体膜损伤为特点。但bnip3是否参与大鼠全脑缺血/再灌注损伤中海马神经元的死亡以及引起细胞死亡的机制目前还不清楚。目前对于bnip3引起细胞死亡的下游分子机制还未明确。AIF是已知的线粒体功能障碍的下游分子之一,参与了caspase非依赖性细胞死亡通路。AIF是存在于线粒体内外膜之间的凋亡相关蛋白。当细胞受到特定的凋亡诱导信号的刺激后,线粒体膜上的PTP打开,允许它们从线粒体释放到胞浆,并转位到核内进而引起DNA的大片段裂解,但AIF本身没有核酶的特性,它的DNA降解作用是通过其它核酶来实现的。EndoG很可能是AIF的相互作用分子。AIF和EndoG参与多种细胞的死亡通路,但其是否是bnip3诱导细胞死亡的下游分子目前尚不明确。本研究观察了脑缺血/再灌注后大鼠海马神经元的死亡情况。采用改良的Pulsinelli四血管闭塞法制做大鼠全脑缺血再灌注模型,通过尼氏染色观察海马神经元的存活状况,与假手术组相比,缺血后7天的海马CA1区有大量神经细胞皱缩,胞核碎裂消失,结构不清,证明我们的模型确实引起海马神经元的死亡。首先,通过Western Blot观察了bnip3在脑缺血/再灌注后不同时间点海马CA1区全细胞以及线粒体中的表达清况。在缺血/再灌注后不同时间点,假手术组于术后24小时麻醉大鼠,断头取脑,分离海马CA1区,提取全细胞及线粒体蛋白样品。全细胞样品的结果显示bnip3单体(20KD)于缺血/再灌注后增加,差别有统计学意义(F=33.117,P=0.000);缺血/再灌注后6,12,24,48小时组bnip3单体(20KD)蛋白的表达水平分别是假手术组的1.51±0.10,1.80±0.14,2.14±0.11,2.46±0.23倍,差别有统计学意义(P<0.05);bnip3双聚体(60KD)在缺血/再灌注后表达水平上调,差别有统计学意义(F=23.113,P=0.000)缺血/再灌注后6,12小时组bnip3双聚体(60KD)蛋白的表达水平分别是假

关键词：脑缺血海马CA1区线粒体 bnip3 AIF caspase非依赖性凋亡

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Upregulation of bnip3 and translocation to mitochondria mediates cyanide-induced apoptosis in cortical cells

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NEUROSCIENCE 2007年第1期150卷 159-167页

作者： Prabhakaran, K. Li, L. Zhang, L. Borowitz, J. L. Isom, G. E. Purdue Univ Dept Med Chem & Mol Pharmacol W Lafayette IN 47907 USA

Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (bnip3), a BcI-2 homology domain 3 (BH3) domain only protein, has been identified as a mitochondrial mediator of hypoxia-induced cell death. Since cyanide produces histotoxic anoxia (chemical hypoxia), the present study was undertaken in primary rat cortical cells to determine involvement of the bnip3 signaling pathway in cyanide-induced death. Over a 20 h exposure KCN increased bnip3 expression, followed by a concentration-related apoptotic death. To determine if bnip3 plays a role in the cell death, expression was either increased with bnip3 cDNA (bnip3(+)) or knocked down with small interfering RNA (RNAi). In bnip3(+) cells, cyanide-induced apoptotic death was markedly enhanced and preceded by reduction of mitochondrial membrane potential (Delta psi(m).), release of cytochrome c from mitochondria and elevated caspase 3 and 7 activity. Pretreatment with the pan-caspase inhibitor N-benzyioxycarbonyl-Ala-Asp-fluoromethyl ketone (zVAD-fmk) suppressed bnip3(+)-mediated cell death, thus confirming a caspase-dependent apoptosis. On the other hand, bnip3 knockdown by RNAi or antagonism of bnip3 by a transmembrane-deleted dominant-negative mutant (bnip3 Delta TM) markedly reduced cell death. Immunohistochemical imaging showed that cyanide stimulated translocation of bnip3 from cytosol to mitochondria and displacement studies with bnip3 Delta TM showed that integration of bnip3 into the mitochondrial outer membrane was necessary for the cell death. In bnip3+ cells, cyclosporin-A, an inhibitor of mitochondrial pore transition, blocked the cyanide-induced reduction of Delta psi(m) and decreased the apoptotic death. These results demonstrate in cortical cells that cyanide induces a rapid upregulation of bnip3 expression, followed by translocation to the mitochondrial outer membrane to reduce At m. This was followed by mitochondrial release of cytochrome c to execute a caspase-dependent cell death. (c) 2007 IBRO. Published by E

关键词： cyanide bnip3 apoptosis neurotoxicity

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