亚硒酸钠通过PI3K/Akt信号通路抑制自吞噬促进NB4细胞凋亡的研究
摘要
硒是人体所必需的微量元素,具有抗癌作用能够诱导多种肿瘤细胞凋亡。大量研究表明:微量元素硒将成为抗肿瘤药物研究领域的一个研究热点。虽然对硒防癌治癌的作用已有报道,但是,对其机理并不十分清楚。本论文将在硒诱导白血病NB4细胞凋亡与自吞噬转换关系上进行研究,探究硒诱导白血病细胞凋亡的分子机理。
自吞噬(Autophagy)是近年研究的一个热点课题。自吞噬是一个细胞将胞质中的老化蛋白或损伤的细胞器送入溶酶体内并将其降解的过程。在应激状态下,这些内容物被重新回收,为细胞提供能量,维持细胞稳态,促进细胞生存。然而过度的自吞噬可导致整个细胞功能的丧失,促进细胞死亡。
本实验室前期研究结果表明,20μM亚硒酸钠能够有效抑制人急性早幼粒白血病NB4细胞的生长增殖并诱发细胞凋亡。基因芯片结果显示该凋亡的发生与线粒体和内质网信号通路相关。而目前已有研究表明自吞噬的发生可能与清除细胞内损伤的线粒体和内质网,促进细胞生存相关。并且,这两条信号通路中的蛋白是联系凋亡与自吞噬的关键调控蛋白。因此,本文诣从自吞噬与凋亡的关系入手,进一步研究亚硒酸钠诱导NB4细胞凋亡的调控机制。从而为亚硒酸钠的临床应用提供有价值的理论依据。
本文对亚硒酸钠诱导NB4细胞凋亡过程中自吞噬与凋亡的关系进行了深入的研究。研究发现在NB4细胞中,自吞噬现象明显,随着亚硒酸钠作用时间的延长,自吞噬水平降低。发现PI3K-Akt信号通路促进了NB4细胞中的自吞噬水平,而自吞噬又促进了NB4细胞的生存。此外,研究还发现自吞噬的抑制剂和亚硒酸钠联用可提高NB4细胞的凋亡率。
研究首先发现,在亚硒酸钠诱导NB4细胞凋亡过程中,自吞噬被抑制。目前对自吞噬究竟是介导细胞生存还是死亡,结论并不一致。研究普遍认为不同的细胞株在不同药物作用下,结果不同。本研究通过电镜,流式细胞仪,丫啶橙染色,免疫印迹等方法充分证明,NB4细胞中的自吞噬现象明显,其相关基因Beclin1和LC3被高表达。而当用亚硒酸钠诱导NB4细胞凋亡时,细胞中自吞噬现象减弱,伴随凋亡率上升。
采用自吞噬抑制剂进一步研究发现,在NB4细胞中抑制自吞噬可促进硒诱导的凋亡。采用自吞噬的抑制剂三甲基腺嘌呤(3-methyladenine,3-MA)与巴佛洛酶素(bafilomycin A1,Baf A1)处理NB4细胞,发现其自吞噬现象减弱。3-MA可抑制自噬泡的形成,而Baf A1可通过抑制溶酶体上的质子泵阻止自噬泡和溶酶体的融合。单独使用3-MA并不能引起凋亡,但Baf A1可以。当我们将这两种自吞噬抑制剂与亚硒酸钠联用处理NB4细胞时,发现NB4细胞的凋亡率与单独被硒处理相比有很大幅度提升。
进一步的机理研究发现,PI3K/Akt/mTOR信号通路促进了自吞噬。本实验室前期研究证明抑制Akt的表达可促进亚硒酸钠诱导NB4细胞凋亡。因此我们在分子水平上分析了PI3K/Akt信号通路。经过亚硒酸钠处理的NB4细胞中,不论在有无自吞噬抑制剂存在的情况下,Akt的磷酸化水平都有显著下降。而且,硒可以抑制Akt下游蛋白mTOR底物p70S6K的磷酸化。更重要的是自吞噬的抑制剂可增强硒对p70S6K磷酸化的抑制程度,并且亚硒酸钠与自吞噬抑制剂联合处理比亚硒酸钠单独处理可更大程度上下调PI3K/Akt信号通路。证明了PI3K/Akt/mTOR信号通路在抑制NB4细胞自吞噬,促进凋亡过程中发挥重要作用。
为进一步研究PI3K/Akt与自吞噬的关系,我们用PI3K的抑制剂LY294002处理NB4细胞,以探求Akt的抑制是否可以抑制自吞噬。结果发现抑制Akt的表达,可以抑制自吞噬。
综上结果证明,亚硒酸钠可通过PI3K/Akt信号通路抑制NB4细胞的自吞噬促进细胞凋亡,并且抑制自吞噬可提高硒诱导NB4细胞的凋亡率。此研究为硒治疗白血病提供了新的理论依据。
Selenium,an essential trace element possessing anti-carcinogenic properties,can induce apoptosis in cancer cells,raising a new idea for its clinical application.
Autophagy is a regulated process that degrades and recycles cellular constituents, where parts of the cytoplasm or entire organelles are sent to lysosomes and are degraded by lysosomal hydrolases.Although autophagy can serve as a protective mechanism against apoptosis and starvation by recycling macromolecules and removing damaged organelles,excessive autophagy results in cell death.
Previous studies discovered that 20μM sodium selenite markedly inhibited the proliferation and induced apoptosis of acute promyelocytic leukemia NB4 cells in a time-dependent manner,cDNA microarray analysis showed that there is a close relationship between apoptosis and signaling pathway of mitochondrialand Endoplasmic reticulum stress(ER stress).Autophagy may be caused by the clearance of damaged mitochondrial and ER,so that can promote survival.In addition,the diverse proteins exist in these pathways are key regulating proteins of autophagy.
However,the mechanisms behind these effects remain elusive.Our research did further studies on the relationship between autophagy and apoptosis,the mechanism that sodium selenite induce apoptosis in NB4 cells and provide valuable evidence for clinical usage for sodium selenite.As a result,this paper did research on the relationship of apoptosis and autophagy,in order to further uncover the mechanism of selenite induced apoptosis and provide valuable basis for the clinical use of selenite.
In this study,we have investigated the role of autophagy in selenium-induced apoptosis in NB4 cells.We first find that autophagy is at a high level in normal NB4 cells,and then is suppressed when treated by sodium selenite.PI3K-Akt signaling pathway promotes the autophagy level in NB4 cells.And autophagy facilitates survival of NB4 cells.Moreover,combination treatment of autophagy inhibitor and selenite can promotes apoptosis ratio when compared to selenite treatment alone.
Whether autophagy plays role for survival or death is still a debated question.People now believe that the role dependents on certain conditions,including medicine and cell type.Autophagy is at a high level in normal NB4 cells and the expression levels of related genes are increased,as measured by electron microscope,acridine orange staining and western blot.However,when NB4 cells are treated by selenite,autophagy is suppressed.
Inhibiting autophagy can facilitate selenite induced apoptosis in NB4 cells.We then use autophagy inhibitor 3- methyladenine(3-MA) and bafilomycin A1(Baf A1) to inhibit autophagy in NB4 cells.3-MA can suppress the formation of autophagic vesicles. And Baf A1 can stop the fusion between autophagosome and lysosome by inhibiting ATP pump on lysosoem.We find that selenite combined with either autophagy inhibitor contributes to the up-regulation of apoptosis,compared to selenite alone treatmnet group.
Our previous studies show that Akt plays a key role in selenite-induced apoptosis in NB4 cells.Additionally,plenty results prove that PI3K/Akt signaling pathway plays an important role in autophagy regulation.As a result,we detect the PI3K/Akt pathway in molecular level,and find that selenite suppresses the phosphorylation in NB4 cells no matter autophagy inhibitor exists or not.In addition,Selenite can inhibit the phosphorylation of p70S6K,which is controlled by mTOR,downstream of Akt.More important,autophagy inhibitor combined selenite inhibits PI3K/Akt pathway in a deeper extent than selenite treatment alone.This indicates the important role of autophagy inhibition and apoptosis promotion played by PI3K/Akt/mTOR.
To further investigate the relationship between PI3K/Akt and autophagy,we use PI3K inhibitor LY294002 to treat NB4 cells,in order to find out whether Akt inhibition can suppress autophagy.Consistently,when the inhibitor of PI3K was applied,the autophagic level significantly decreased.
In summary,sodium selenite increases NB4 cell apoptosis by autophagy inhibition through PI3K/Akt,and the inhibition of autophagy contributes to the up-regulation of apoptosis.
自吞噬(Autophagy)是近年研究的一个热点课题。自吞噬是一个细胞将胞质中的老化蛋白或损伤的细胞器送入溶酶体内并将其降解的过程。在应激状态下,这些内容物被重新回收,为细胞提供能量,维持细胞稳态,促进细胞生存。然而过度的自吞噬可导致整个细胞功能的丧失,促进细胞死亡。
本实验室前期研究结果表明,20μM亚硒酸钠能够有效抑制人急性早幼粒白血病NB4细胞的生长增殖并诱发细胞凋亡。基因芯片结果显示该凋亡的发生与线粒体和内质网信号通路相关。而目前已有研究表明自吞噬的发生可能与清除细胞内损伤的线粒体和内质网,促进细胞生存相关。并且,这两条信号通路中的蛋白是联系凋亡与自吞噬的关键调控蛋白。因此,本文诣从自吞噬与凋亡的关系入手,进一步研究亚硒酸钠诱导NB4细胞凋亡的调控机制。从而为亚硒酸钠的临床应用提供有价值的理论依据。
本文对亚硒酸钠诱导NB4细胞凋亡过程中自吞噬与凋亡的关系进行了深入的研究。研究发现在NB4细胞中,自吞噬现象明显,随着亚硒酸钠作用时间的延长,自吞噬水平降低。发现PI3K-Akt信号通路促进了NB4细胞中的自吞噬水平,而自吞噬又促进了NB4细胞的生存。此外,研究还发现自吞噬的抑制剂和亚硒酸钠联用可提高NB4细胞的凋亡率。
研究首先发现,在亚硒酸钠诱导NB4细胞凋亡过程中,自吞噬被抑制。目前对自吞噬究竟是介导细胞生存还是死亡,结论并不一致。研究普遍认为不同的细胞株在不同药物作用下,结果不同。本研究通过电镜,流式细胞仪,丫啶橙染色,免疫印迹等方法充分证明,NB4细胞中的自吞噬现象明显,其相关基因Beclin1和LC3被高表达。而当用亚硒酸钠诱导NB4细胞凋亡时,细胞中自吞噬现象减弱,伴随凋亡率上升。
采用自吞噬抑制剂进一步研究发现,在NB4细胞中抑制自吞噬可促进硒诱导的凋亡。采用自吞噬的抑制剂三甲基腺嘌呤(3-methyladenine,3-MA)与巴佛洛酶素(bafilomycin A1,Baf A1)处理NB4细胞,发现其自吞噬现象减弱。3-MA可抑制自噬泡的形成,而Baf A1可通过抑制溶酶体上的质子泵阻止自噬泡和溶酶体的融合。单独使用3-MA并不能引起凋亡,但Baf A1可以。当我们将这两种自吞噬抑制剂与亚硒酸钠联用处理NB4细胞时,发现NB4细胞的凋亡率与单独被硒处理相比有很大幅度提升。
进一步的机理研究发现,PI3K/Akt/mTOR信号通路促进了自吞噬。本实验室前期研究证明抑制Akt的表达可促进亚硒酸钠诱导NB4细胞凋亡。因此我们在分子水平上分析了PI3K/Akt信号通路。经过亚硒酸钠处理的NB4细胞中,不论在有无自吞噬抑制剂存在的情况下,Akt的磷酸化水平都有显著下降。而且,硒可以抑制Akt下游蛋白mTOR底物p70S6K的磷酸化。更重要的是自吞噬的抑制剂可增强硒对p70S6K磷酸化的抑制程度,并且亚硒酸钠与自吞噬抑制剂联合处理比亚硒酸钠单独处理可更大程度上下调PI3K/Akt信号通路。证明了PI3K/Akt/mTOR信号通路在抑制NB4细胞自吞噬,促进凋亡过程中发挥重要作用。
为进一步研究PI3K/Akt与自吞噬的关系,我们用PI3K的抑制剂LY294002处理NB4细胞,以探求Akt的抑制是否可以抑制自吞噬。结果发现抑制Akt的表达,可以抑制自吞噬。
综上结果证明,亚硒酸钠可通过PI3K/Akt信号通路抑制NB4细胞的自吞噬促进细胞凋亡,并且抑制自吞噬可提高硒诱导NB4细胞的凋亡率。此研究为硒治疗白血病提供了新的理论依据。
Selenium,an essential trace element possessing anti-carcinogenic properties,can induce apoptosis in cancer cells,raising a new idea for its clinical application.
Autophagy is a regulated process that degrades and recycles cellular constituents, where parts of the cytoplasm or entire organelles are sent to lysosomes and are degraded by lysosomal hydrolases.Although autophagy can serve as a protective mechanism against apoptosis and starvation by recycling macromolecules and removing damaged organelles,excessive autophagy results in cell death.
Previous studies discovered that 20μM sodium selenite markedly inhibited the proliferation and induced apoptosis of acute promyelocytic leukemia NB4 cells in a time-dependent manner,cDNA microarray analysis showed that there is a close relationship between apoptosis and signaling pathway of mitochondrialand Endoplasmic reticulum stress(ER stress).Autophagy may be caused by the clearance of damaged mitochondrial and ER,so that can promote survival.In addition,the diverse proteins exist in these pathways are key regulating proteins of autophagy.
However,the mechanisms behind these effects remain elusive.Our research did further studies on the relationship between autophagy and apoptosis,the mechanism that sodium selenite induce apoptosis in NB4 cells and provide valuable evidence for clinical usage for sodium selenite.As a result,this paper did research on the relationship of apoptosis and autophagy,in order to further uncover the mechanism of selenite induced apoptosis and provide valuable basis for the clinical use of selenite.
In this study,we have investigated the role of autophagy in selenium-induced apoptosis in NB4 cells.We first find that autophagy is at a high level in normal NB4 cells,and then is suppressed when treated by sodium selenite.PI3K-Akt signaling pathway promotes the autophagy level in NB4 cells.And autophagy facilitates survival of NB4 cells.Moreover,combination treatment of autophagy inhibitor and selenite can promotes apoptosis ratio when compared to selenite treatment alone.
Whether autophagy plays role for survival or death is still a debated question.People now believe that the role dependents on certain conditions,including medicine and cell type.Autophagy is at a high level in normal NB4 cells and the expression levels of related genes are increased,as measured by electron microscope,acridine orange staining and western blot.However,when NB4 cells are treated by selenite,autophagy is suppressed.
Inhibiting autophagy can facilitate selenite induced apoptosis in NB4 cells.We then use autophagy inhibitor 3- methyladenine(3-MA) and bafilomycin A1(Baf A1) to inhibit autophagy in NB4 cells.3-MA can suppress the formation of autophagic vesicles. And Baf A1 can stop the fusion between autophagosome and lysosome by inhibiting ATP pump on lysosoem.We find that selenite combined with either autophagy inhibitor contributes to the up-regulation of apoptosis,compared to selenite alone treatmnet group.
Our previous studies show that Akt plays a key role in selenite-induced apoptosis in NB4 cells.Additionally,plenty results prove that PI3K/Akt signaling pathway plays an important role in autophagy regulation.As a result,we detect the PI3K/Akt pathway in molecular level,and find that selenite suppresses the phosphorylation in NB4 cells no matter autophagy inhibitor exists or not.In addition,Selenite can inhibit the phosphorylation of p70S6K,which is controlled by mTOR,downstream of Akt.More important,autophagy inhibitor combined selenite inhibits PI3K/Akt pathway in a deeper extent than selenite treatment alone.This indicates the important role of autophagy inhibition and apoptosis promotion played by PI3K/Akt/mTOR.
To further investigate the relationship between PI3K/Akt and autophagy,we use PI3K inhibitor LY294002 to treat NB4 cells,in order to find out whether Akt inhibition can suppress autophagy.Consistently,when the inhibitor of PI3K was applied,the autophagic level significantly decreased.
In summary,sodium selenite increases NB4 cell apoptosis by autophagy inhibition through PI3K/Akt,and the inhibition of autophagy contributes to the up-regulation of apoptosis.
引文
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42. Axel H. Schonthal, Endoplasmic reticulum stress and autophagy as targets for cancer therapy. Cancer Letters, 2008,275(2): 163-169
43. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammar backJA, Urano F, Imaizumi K. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol, 2006,26:9220-9231
44. Luigi Moretti, Yong I Cha, Kenneth John Niermann, Bo Lu. Switch between apoptosis and autophagy: Radiation-induced endoplasmic reticulum stress? Cell Cycle, 2007, 6: 7793-7798
45. Guan L, Han B, Li Z, Hua F, Huang F, Wei W, Yang Y, Xu C. Sodium selenite induces apoptosis by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction in human acute promyelocytic leukemia NB4 cells.Apoptosis. 2009, 14(2):218-25.
46. Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: A matter of life or death. Cell Death Differ, 2006,13: 363-373
47. Lu Zuo、 Jian Li、Yang yang, et al, Sodium selenite induces apoptosis in acute promyelocytic leukemia-derived NB4 cells by a caspase-3-dependent mechanism and a redox pathway different from that of arsenic troxide. Annals of Hematology, 2004; 83(12):756-758.
48. Wang jian , Zuo lu , Shen ti, et al, l .Induction of apoptosis by Sodium Selenite in human acute promyelelocytic leukemia NB4 cell: Involvement of oxidative stress and Mitochondria Joural of Trace Elements in Medicine and Biology, 2003,17(1):19-26
49. Noboru Mizushima. Autophagy: process and function. Genes & Development, 2007, 21,2871-2873
50. Daniel J. Klionsky. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Bio. 2007, 8,931-937
51. M. Chiara Maiuri, Einat Zalckvar, Adi Kimchi and Guido Kroemer. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Bio. 2007, 8, 741-950
52. Marte BM, Downward J. PKB/Akt: Connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci. 1997,22, 355-358.
53. Hennessy BT, Smith DL, Ram PT. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov, 2005,4,988-1004
54. Xuehuo Zeng and Timothy J. Kinsella. Mammalian target of Rapamycin and S6 Kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res. 2008, 68, 2384-2390
55. Klionsky DJ, Meijer AJ, Codogno P..Autophagy and p70S6 kinase. Autophagy, 2005, 1,59-60
56. Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P. Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem. 2000,275,992-81-64
57. Arico S, Petiot A, Bauvy C, et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem, 2001, 276, 35243-6
58. Bursch, W.. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ, 2001, 8, 569-581.
59. Seglen, P.O., and P.B. Gordon.. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl. Acad.Sci. USA, 1982, 79, 1889-1892
60. Bowman, E.J., A. Siebers, and K. Altendorf. Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc. Natl. Acad. Sci. USA, 1988, 85, 7972-7976
61. Meijer AJ and Codogno P. Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol, 2004, 36: 2445-2462.
62. emasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta. 1998,1366,177-196.
63. Qiao Cui, Shin-ichi Tashiro, Satoshi Onodera, and Takashi Ikejima Augmentation of Oridonin-Induced Apoptosis Observed With Reduced Autophagy. J Pharmacol Sci. 2006, 101,230-239
64. Ravi K. Amaravadi. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 2007,117, 326-336
65. Patricia Boya. Inhibition of Macroautophagy Triggers Apoptosis. MCB, 2004, 25, 1025-1040
66. Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tμMorigenesis. Cancer Cell. 2006,10, 51-64
67. Dourmashkin LR, Allen PD, Gray AB, Newland AC, Kelsey SM. Inhibition of autophagy abrogates tumour necrosis factor a induced apoptosis in human T-lymphoblastic leukaemic cells. Br J Haematol, 1997, 98, 673-685.
[1] Noboru Mizushima. Autophagy: process and function. Genes & Development, Nov.2007,21:2861-2873.
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[3] Yoshinori Ohsumi. Molecular dissection of autophagy: two ubiquitin-like system. Nat. Rev. Molecular Cell Biology, Mar 2001, 2:211-216.
[4] Levine, B & Klionsky. Development by self-digestion:molecular mechanisms and biological functions of autophagy. Dev. Cell, 2007, 6: 463-477.
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[10] Qadir MA, Kwok B, Dragowska WH, To KH, Le D, Bally MB et al. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res Treat, 2008, in press.
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42. Axel H. Schonthal, Endoplasmic reticulum stress and autophagy as targets for cancer therapy. Cancer Letters, 2008,275(2): 163-169
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49. Noboru Mizushima. Autophagy: process and function. Genes & Development, 2007, 21,2871-2873
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53. Hennessy BT, Smith DL, Ram PT. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov, 2005,4,988-1004
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55. Klionsky DJ, Meijer AJ, Codogno P..Autophagy and p70S6 kinase. Autophagy, 2005, 1,59-60
56. Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P. Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem. 2000,275,992-81-64
57. Arico S, Petiot A, Bauvy C, et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem, 2001, 276, 35243-6
58. Bursch, W.. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ, 2001, 8, 569-581.
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63. Qiao Cui, Shin-ichi Tashiro, Satoshi Onodera, and Takashi Ikejima Augmentation of Oridonin-Induced Apoptosis Observed With Reduced Autophagy. J Pharmacol Sci. 2006, 101,230-239
64. Ravi K. Amaravadi. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 2007,117, 326-336
65. Patricia Boya. Inhibition of Macroautophagy Triggers Apoptosis. MCB, 2004, 25, 1025-1040
66. Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tμMorigenesis. Cancer Cell. 2006,10, 51-64
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[1] Noboru Mizushima. Autophagy: process and function. Genes & Development, Nov.2007,21:2861-2873.
[2] M.Chiara Maiuri. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature rev. Molecular cell biology, Sep.2007, 8: 741-751.
[3] Yoshinori Ohsumi. Molecular dissection of autophagy: two ubiquitin-like system. Nat. Rev. Molecular Cell Biology, Mar 2001, 2:211-216.
[4] Levine, B & Klionsky. Development by self-digestion:molecular mechanisms and biological functions of autophagy. Dev. Cell, 2007, 6: 463-477.
[5] Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: cross talk between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007, 8: 741-752.
[6] Rodriguez-Enriquez S, Kim I, Currin RT, Lemasters JJ. Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy 2006, 2: 39-46.
[7] Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007,117: 326-336.
[8] Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res 2008, 68: 1485-1494.
[9] Tiwari M, Bajpai VK, Sahasrabuddhe AA, Kumar A, Sinha RA, Behari S et al. Inhibition of N-(4-hydroxyphenyl)retinamide-induced autophagy at a lower dose enhances cell death in malignant glioma cells. Carcinogenesis 2008,29: 600-609.
[10] Qadir MA, Kwok B, Dragowska WH, To KH, Le D, Bally MB et al. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res Treat, 2008, in press.
[11] Li M, Jiang X, Liu D, Na Y, Gao GF, Xi Z. Autophagy protects LNCaP cells under androgen deprivation conditions. Autophagy, 2008,4: 54-60.
[12] Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y et al. Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res,2007,67:9677-9684.
[13]Han J,Hou W,Goldstein LA,Lu C,Stolz DB,Yin XM et al.Involvement of protective autophagy in TRAIL-resistance of apoptosis defective tumor cells.J Biol Chem,2008,283:19665-19677.
[14]Gonzalez-Polo,R.A.et al.The apoptosis/autophagy paradox:autophagic vacuolization before apoptotic death.J.Cell Sci,2005,118:3091-3102
[15]Robin M.et al.Role of autophagy in cancer;Nature Reviews Cancer;Nov.2007.
[16]Takao Kanzawa,Induction of Autophagic Cell Death in Malignant Glioma Cells by Arsenic Trioxide;Cancer Research,May 1,2003,63:2103-2108
[17]Azad MB,Chen Y Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3.Autophagy:Mar-Apr;2008,4(2):195-204
[18]Fazi B,Bursch W,Fimia GM,Fenretinide induces autophagic cell death in caspase-defective breast cancer cells.Autophagy,Feb 2008 4(4)
[19]Scherz-Shouval,R.et al.Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4.EMBO J.2007,26:1749-1760
[20]Lavieu,G.et al.Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation.J.Biol.Chem,2006,281:8518-8527
[21]Feng,Z.,The coordinate regulation of the p53 and mTOR pathways in cells.Proc.Natl Acad.Sci,USA 2005,102:8204-8209
[22]Adams,J.M.& Hardwick,J.M.Upgrading the BCL-2 network.Nature Cell Biol,2006,8:1317-1319
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[24]Raveh,T.,Droguett,G.,Horwitz,M.S.,Depinho,R.A.& Kimchi,A.DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation.Nature Cell Biol.2001,3:1-7
[25]Reef,S.et al.A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death.Mol.Cell,2006,22:463-475
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