國立臺灣師範大學博碩士論文全文系統

簡易檢索 / 詳目顯示

回結果列表

研究生：	謝長亨 Hsieh, Chang-Heng
論文名稱：	三唑化合物作為自噬促進劑用於疾病治療 Triazole derivatives as autophagy enhancers
指導教授：	方剛 Fang, Kang
學位類別：	博士 Doctor
系所名稱：	生命科學系 Department of Life Science
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	161
中文關鍵詞：	細胞自噬、多麩醯胺酸、聚集物清除、三唑化合物、JNK訊息傳遞、神經退化疾病、人類非小細胞肺癌細胞、細胞凋亡
英文關鍵詞：	autophagic flux, polyglutamine, aggregates clearance, triazole, JNK pathway, neuronal disorders, human non-small-cell-lung-cancer cells, apoptosis
DOI URL：	https://doi.org/10.6345/NTNU202203506
論文種類：	學術論文
相關次數：	點閱：127 下載：6
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

本論文目的是鑑定三唑衍生物潛在用於治療神經退化疾病及非小細肺癌細胞的藥物。多麩醯胺酸造成的神經退化性疾病是因為神經細胞中基因座上出現過度CAG三核甘酸的重複序列所導致的疾病。利用增加細胞自噬清除多麩醯胺酸堆積，是一種可能的方式用來治療多麩醯胺酸相關神經疾病。在第一部分的論文中，利用表現多麩醯胺酸的細胞模式篩選一系列的候選藥物。從一系列三唑衍生物中篩選出化合物的藥物OC-13,它可以透過增強自噬特性，清除外來質體衍生的蛋白質ΔC-TBP-Q79-EGFP或Httex1-Q97-GFP造成多麩醯胺酸堆積，卻不會影響細胞活性。由螢光顯微鏡下觀察，表現擴增多麩醯胺酸的細胞經OC-13處理增加自噬小體，會清除超過５０％的蛋白質堆積。由西方墨點法分析顯示，OC-13促進LC3-I轉換為LC3-II以增進自噬體形成，而自噬抑制劑能阻斷OC-13清除多麩醯胺酸的功能。
論文第二部分利用增強細胞自噬主導的第二型計畫性細胞死亡可以用作於癌症的治療。透過細胞活性分析, colony forming assay, Annexin V染色及西方墨點法分析，可以確認另一個三唑衍生物BTO會抑制人類非小細胞肺癌細胞的增生，並能隨著時間及濃度誘導自噬相關蛋白，並且促進凋亡，這都是透過自噬小體增加與溶酶體的形成。利用Annexin V染色及西方墨點法分析可以顯示促進自噬的BTO造成肺癌細胞的凋亡。此外由腫瘤組織的西方墨點分析和螢光顯微鏡中顯示，BTO可以抑制在小鼠模型中異種移植的A549腫瘤生長，並且誘導凋亡和自噬標記物的增生。

這兩種三唑衍生物化合物可以是抑制人類疾病的一種潛在治療藥劑。

Strategies that enhance autophagy clearance of polyQ accumulation have become an attractive approach to revive neuronal cell viabilities. In the part I of the dissertation, a selected autophagic enhancer candidate was identified as a cell model for polyQ aggregation clearance. The polyQ diseases were caused by expansion of CAG trinucleotide repeats in the coding region of gene. After screening a series of triazole derivatives, a newly identified synthetic compound, 5,5′-(4,4′-(1,3-phenylene-bis(oxy))-bis(methylene)-bis(1H-1,2,3-triazole-4,1-diyl))-bis(methylene)-bis(3-(naphthalene-1-yl)-oxazolidin-2-one (OC-13), was shown capable of enhancing clearance of the aggregated polyQ in neuroblastoma cells. Human neuroblastoma cells SK-N-SH with ectopic expression of ΔC-TBP-Q79-EGFP or Httex1-Q97-GFP mutant protein can be cleared of mutated aggregates without affecting cell viabilities. Treatment of OC-13 increased autophagosome formation and more than 50% the accumulated aggregates were eradicated as determined by fluorescence microscopy. Western blot showed that OC-13 converted LC3-I to LC3-II in the transfected cells and activated autophagy-mediated elimination of polyQ aggregation. The effects were repressed by autophagic inhibitors.

Autophagic enhancer is also a valid treatment strategy as cancer therapeutics. In the part II of the dissertation, another newly identified triazole derivative compound, 4-((5-benzyl-1H-1,2,4-triazol-3-yl)-methyl)-7-methoxy-2H-benzo[b][1,4]-oxazin-3(4H)-one (BTO), was found inhibiting the growth of human NSCLC cells. BTO induced autophagic characteristics and inhibited cell growth as shown in MTT evaluation, colony forming assay and Western blot. The compound induced autophagosome and autolysosome formation. More experiments with Annexin V staining and Western blot showed that the drug induced apoptotic cell death that was related to autophagy activation. Furthermore, BTO suppressed the growth of xenograft tumors by activating autophagy-mediated apoptosis as shown in Western blot and fluorescence microscopy of tumor tissue specimen staining.

The triazole derivatives OC-13 and BTO can be of potential therapeutic values to treat human diseases.

INDEX    5
CHAPTER I ABSTRACT    11
CHAPTER II 中文摘要    13
LIST OF ABBREVIATIONS    15
CHAPTER III AUTOPHAGY    17
CHAPTER IV    19
PART I THE APPLICATION AND MECHANISMS TO TREAT POLYGLUTAMINE DISEASES    19
I.    INTRODUCTION    19
1.    Protein aggregation diseases    19
2.    Triazole derivatives and neurodegeneration    19
3.    Autophagy and protein aggregation diseases    20
II.    MATERIAL AND METHOD    21
1.    Cell culture    21
2.    Plasmid and transfection    21
3.    Reagents    22
4.    FACScalibur analysis    24
5.    Immunoblotting    24
6.    Quantification of aggregation dots    25
7.    Confocal microscopy detection    25
8.    Statistical analysis    26
III.    RESULTS    27
1.    Establishment of inducible polyQ stable cell lines    27
2.    Autophagic enhancer screening    27
3.    More evidence of OC-13-activated autophagy.    28
4.    Amelioration of Q79-EGFP aggregates by OC-13    29
5.    The autophagic clearance is related to JNK signaling pathway activation    30
6.    Clearance of the Q79-EGFP aggregates by JNK-mediated autophagy    30
7.    Exclusion of nucleus polyQ aggregation    31
8.    Transient Httex1 polyQ transfection    31
9.    OC-13-induced autophagy in cells transfected with Httex1-Q97    32
10.    Phosphorylation of JNK and Akt are increased by OC-13 in Httex1-Q97 transfected cells    33
11.    OC-13 decreased Httex1-Q97 aggregations    33
12.    Elimination of Httex1-Q97 aggregation by OC-13-mediated autophagy    34
13.    Elimination of aggregates by JNK-mediated autophagy    34
IV.    DISCUSSION    36
CHAPTER V    40
PART II THE APPLICATION AND MECHANISMS TO TREAT HUMAN NON-SMALL CELL LUNG CANCER CELLS    40
I.    INTRODUCTION    40
1.    Lung cancer    40
2.    Triazole derivatives and cancer    40
3.    Autophagic cell death    41
4.    Cancer and autophagy    41
II.    MATERIAL AND METHOD    42
1.    Cell culture    42
2.    Plasmid and transfection    43
3.    Reagents    43
4.    FACScalibur analysis    47
5.    Immunoblotting    47
6.    Animals and treatments    48
7.    Histochemical staining    48
8.    Cell viability assay    49
9.    Colony forming assay    49
10.    Statistical analysis    49
III.    RESULTS    51
1.    BTO inhibited cell growth by apoptosis    51
2.    Enhancement of apoptosis and autophagy characters by BTO    51
3.    Autophagy-mediated apoptosis by BTO    52
4.    BTO increase ROS in A549 cells    52
5.    BTO repressed growth in nude mice bearing xenograft tumors    53
IV.    DISCUSSION    55
CHAPTER VI CONCLUSION    58
CHAPTER VII FIGURES    60
Figure 1. Establishment of polyQ disease cell models.    61
Figure 2. Screening of autophagy enhancing chemicals    63
Figure 3. Changes of cell viability and aggregation intensities by candidate compounds.    65
Figure 4. The variations of autophagy markers.    67
Figure 5. The candidate chemical OC-13 and cell viability determination    68
Figure 6. Activation of lysosome by OC-13.    71
Figure 7. Induction of autophagy markers by OC-13.    73
Figure 8. Inhibition of autophagy by Baf A1.    74
Figure 9. Autophagosome formation and aggregates clearance by OC-13.    76
Figure 10. Elimination of Q79 aggregation dots by OC-13.    77
Figure 11. Elimination of the insoluble EGFP by OC-13.    79
Figure 12. Activation of JNK pathway.    80
Figure 13. Elimination of Q79 aggregation by JNK pathway and autophagy.    82
Figure 14. Elimination of the insoluble EGFP as affected by inhibitors.    83
Figure 15. The increase of autophagosomes by JNK pathway.    85
Figure 16. Elimination of nucleus Q79 aggregation.    88
Figure 17. Clearance of nucleus Q79 aggregation by autophagy and JNK pathway.    90
Figure 18. Establishment of Httex1 Q25 and Q97 cell models.    91
Figure 19. Increasing of autolysosome by OC-13 in Httex1-Q25 and Q97-transfected cells.    93
Figure 20. Activation of lysosomes by OC-13 in Httex1-Q97 transfected cells.    95
Figure 21. Formation of autophagosome in Httex1-Q97 transfected cells.    96
Figure 22. Induction of autophagic markers in Httex1-Q97 transfected cells by OC-13.    98
Figure 23. Maintenance of cell viability in Httex1-Q97 transfected cells.    100
Figure 24. Activation of JNK, Akt and S6K in Httex1-Q97 transfected cells.    101
Figure 25. Elimination of aggregations in Httex1-Q97 transfected cells.    103
Figure 26. Elimination of the insoluble Httex1-Q97 aggregates by OC-13.    105
Figure 27. Clearance inhibition of aggregation.    107
Figure 28. Clearance inhibition of insoluble Httex1-Q97.    109
Figure 29. Elimination of Httex1 aggregation dots by JNK pathway and autophagy.    111
Figure 30. The increase of autophagosomes by JNK pathway in Httex1-Q97 transfected cells.    112
Figure 31. Summary of OC-13 induced polyQ clearance by autophagy.    113
FIGURE II    114
Figure 32. Inhibition of cell proliferation in human non-small cell lung cancer cells.    115
Figure 33. Activation of apoptosis by BTO.    118
Figure 34. Activation of autophagy and apoptosis by BTO.    119
Figure 35. Apoptosis and autophagy in adenocarcinoma.    121
Figure 36. Formation of autophagosome and autolysosome by BTO.    123
Figure 37. Repression of autophagic flux by 3-MA.    125
Figure 38. Inhibition of BTO-mediated apoptosis by 3-MA.    127
Figure 39. BTO-induced autophagic apoptosis in A549.    128
Figure 40. Increase of ROS intensity by BTO.    130
Figure 41. Inhibition of autophagy by NAC.    132
Figure 42. Inhibition of tumor growth in nude mice xenografts.    134
Figure 43. Increase of apoptosis in nude mice xenografts.    136
Figure 44. Decrease of proliferation and increase of autophagy in tumor.    138
Figure 45. Promotion of apoptosis marker in tumors.    140
Figure 46. Summary of BTO induced autophagy.    141
CHAPTER VIII REFERENCE    142
CHAPTER IX    APPENDIX    152
                                

1. Ristic B, Bosnjak M, Arsikin K, Mircic A, Suzin-Zivkovic V, Bogdanovic A, Perovic V, Martinovic T, Kravic-Stevovic T, Bumbasirevic V, et al: Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells. Exp Cell Res 2014, 326:90-102.
2. Hyttinen JM, Amadio M, Viiri J, Pascale A, Salminen A, Kaarniranta K: Clearance of misfolded and aggregated proteins by aggrephagy and implications for aggregation diseases. Ageing Res Rev 2014, 18C:16-28.
3. Mizushima N: Autophagy: process and function. Genes Dev 2007, 21:2861-2873.
4. Xie Z, Klionsky DJ: Autophagosome formation: core machinery and adaptations. Nat Cell Biol 2007, 9:1102-1109.
5. Marino G, Fernandez AF, Cabrera S, Lundberg YW, Cabanillas R, Rodriguez F, Salvador-Montoliu N, Vega JA, Germana A, Fueyo A, et al: Autophagy is essential for mouse sense of balance. J Clin Invest 2010, 120:2331-2344.
6. Wesselborg S, Stork B: Autophagy signal transduction by ATG proteins: from hierarchies to networks. Cell Mol Life Sci 2015, 72:4721-4757.
7. Jaeger PA, Wyss-Coray T: All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol Neurodegener 2009, 4:16.
8. Tanida I, Ueno T, Kominami E: LC3 and Autophagy. Methods Mol Biol 2008, 445:77-88.
9. Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T: Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol 2009, 452:181-197.
10. Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ, Henske EP: Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 2011, 108:12455-12460.
11. Kang R, Zeh HJ, Lotze MT, Tang D: The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011, 18:571-580.
12. Chen Y, Klionsky DJ: The regulation of autophagy - unanswered questions. J Cell Sci 2011, 124:161-170.
13. Underwood BR, Imarisio S, Fleming A, Rose C, Krishna G, Heard P, Quick M, Korolchuk VI, Renna M, Sarkar S, et al: Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Hum Mol Genet 2010, 19:3413-3429.
14. Sarkar S: Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans 2013, 41:1103-1130.
15. He C, Zhu H, Li H, Zou MH, Xie Z: Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes 2013, 62:1270-1281.
16. Jiang P, Mizushima N: Autophagy and human diseases. Cell Res 2014, 24:69-79.
17. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006, 441:885-889.
18. Rubinsztein DC, Bento CF, Deretic V: Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J Exp Med 2015, 212:979-990.
19. Jacob JA, Salmani JM, Jiang Z, Feng L, Song J, Jia X, Chen B: Autophagy: An overview and its roles in cancer and obesity. Clin Chim Acta 2017.
20. Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC: Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 2009, 16:46-56.
21. La Spada AR, Weydt P, Pineda VV: Huntington's Disease Pathogenesis: Mechanisms and Pathways. In Neurobiology of Huntington's Disease: Applications to Drug Discovery. Edited by Lo DC, Hughes RE. Boca Raton (FL); 2011: Frontiers in Neuroscience].
22. Barton S, Jacak R, Khare SD, Ding F, Dokholyan NV: The length dependence of the polyQ-mediated protein aggregation. J Biol Chem 2007, 282:25487-25492.
23. Shao J, Diamond MI: Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum Mol Genet 2007, 16 Spec No. 2:R115-123.
24. Lu K, Psakhye I, Jentsch S: Autophagic clearance of polyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family. Cell 2014, 158:549-563.
25. Ripaud L, Chumakova V, Antonin M, Hastie AR, Pinkert S, Korner R, Ruff KM, Pappu RV, Hornburg D, Mann M, et al: Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome. Proc Natl Acad Sci U S A 2014, 111:18219-18224.
26. El Shora HM, Ali AS: Plant growth regulators induced urease activity in Cucurbita pepo L. cotyledons. Acta Biol Hung 2016, 67:53-63.
27. Wang X, Dai ZC, Chen YF, Cao LL, Yan W, Li SK, Wang JX, Zhang ZG, Ye YH: Synthesis of 1,2,3-triazole hydrazide derivatives exhibiting anti-phytopathogenic activity. Eur J Med Chem 2016, 126:171-182.
28. Rosim FE, Persike DS, Nehlig A, Amorim RP, de Oliveira DM, Fernandes MJ: Differential neuroprotection by A(1) receptor activation and A(2A) receptor inhibition following pilocarpine-induced status epilepticus. Epilepsy Behav 2011, 22:207-213.
29. Kamalinia G, Khodagholi F, Shaerzadeh F, Tavssolian F, Chaharband F, Atyabi F, Sharifzadeh M, Amini M, Dinarvand R: Cationic albumin-conjugated chelating agent as a novel brain drug delivery system in neurodegeneration. Chem Biol Drug Des 2015, 86:1203-1214.
30. Saiki S, Sasazawa Y, Imamichi Y, Kawajiri S, Fujimaki T, Tanida I, Kobayashi H, Sato F, Sato S, Ishikawa K, et al: Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy 2011, 7:176-187.
31. Shin BH, Lim Y, Oh HJ, Park SM, Lee SK, Ahnn J, Kim do H, Song WK, Kwak TH, Park WJ: Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy. PLoS One 2013, 8:e64953.
32. Kara NZ, Toker L, Agam G, Anderson GW, Belmaker RH, Einat H: Trehalose induced antidepressant-like effects and autophagy enhancement in mice. Psychopharmacology (Berl) 2013, 229:367-375.
33. Edinger AL, Thompson CB: Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 2002, 13:2276-2288.
34. Lee GC, Lin CH, Tao YC, Yang JM, Hsu KC, Huang YJ, Huang SH, Kung PJ, Chen WL, Wang CM, et al: The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment. Neurotoxicology 2015, 48:120-130.
35. Xu C, Li X, Wang F, Weng H, Yang P: Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis. Am J Physiol Endocrinol Metab 2013, 305:E667-678.
36. Lee LC, Chen CM, Chen FL, Lin PY, Hsiao YC, Wang PR, Su MT, Hsieh-Li HM, Hwang JC, Wu CH, et al: Altered expression of HSPA5, HSPA8 and PARK7 in spinocerebellar ataxia type 17 identified by 2-dimensional fluorescence difference in gel electrophoresis. Clin Chim Acta 2009, 400:56-62.
37. Lee LC, Chen CM, Wang PR, Su MT, Lee-Chen GJ, Chang CY: Role of high mobility group box 1 (HMGB1) in SCA17 pathogenesis. PLoS One 2014, 9:e115809.
38. Chikte S, Panchal N, Warnes G: Use of LysoTracker dyes: a flow cytometric study of autophagy. Cytometry A 2014, 85:169-178.
39. Moronetti Mazzeo LE, Dersh D, Boccitto M, Kalb RG, Lamitina T: Stress and aging induce distinct polyQ protein aggregation states. Proc Natl Acad Sci U S A 2012, 109:10587-10592.
40. Lecerf JM, Shirley TL, Zhu Q, Kazantsev A, Amersdorfer P, Housman DE, Messer A, Huston JS: Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease. Proc Natl Acad Sci U S A 2001, 98:4764-4769.
41. Chazotte B: Labeling lysosomes in live cells with LysoTracker. Cold Spring Harb Protoc 2011, 2011:pdb prot5571.
42. Eskelinen EL, Saftig P: Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta 2009, 1793:664-673.
43. Lee GC, Lin CH, Tao YC, Yang JM, Hsu KC, Huang YJ, Huang SH, Kung PJ, Chen WL, Wang CM, et al: The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment. Neurotoxicology 2015, 48:120-130.
44. Myeku N, Figueiredo-Pereira ME: Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: association with sequestosome 1/p62. J Biol Chem 2011, 286:22426-22440.
45. Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, Wanker EE: Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 2001, 12:1393-1407.
46. Myeku N, Metcalfe MJ, Huang Q, Figueiredo-Pereira M: Assessment of proteasome impairment and accumulation/aggregation of ubiquitinated proteins in neuronal cultures. Methods Mol Biol 2011, 793:273-296.
47. Kudchodkar SB, Yu Y, Maguire TG, Alwine JC: Human cytomegalovirus infection induces rapamycin-insensitive phosphorylation of downstream effectors of mTOR kinase. J Virol 2004, 78:11030-11039.
48. Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M, Gretzmeier C, Dengjel J, Piacentini M, Fimia GM, Cecconi F: mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol 2013, 15:406-416.
49. Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, et al: SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 2001, 98:13681-13686.
50. Wu YT, Tan HL, Shui G, Bauvy C, Huang Q, Wenk MR, Ong CN, Codogno P, Shen HM: Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 2010, 285:10850-10861.
51. Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB: Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest 1999, 104:733-741.
52. Han YH, Moon HJ, You BR, Park WH: The effect of MG132, a proteasome inhibitor on HeLa cells in relation to cell growth, reactive oxygen species and GSH. Oncol Rep 2009, 22:215-221.
53. Iwata A, Nagashima Y, Matsumoto L, Suzuki T, Yamanaka T, Date H, Deoka K, Nukina N, Tsuji S: Intranuclear degradation of polyglutamine aggregates by the ubiquitin-proteasome system. J Biol Chem 2009, 284:9796-9803.
54. Crowley LC, Scott AP, Marfell BJ, Boughaba JA, Chojnowski G, Waterhouse NJ: Measuring Cell Death by Propidium Iodide Uptake and Flow Cytometry. Cold Spring Harb Protoc 2016, 2016:pdb prot087163.
55. Bertoni A, Giuliano P, Galgani M, Rotoli D, Ulianich L, Adornetto A, Santillo MR, Porcellini A, Avvedimento VE: Early and late events induced by polyQ-expanded proteins: identification of a common pathogenic property of polYQ-expanded proteins. J Biol Chem 2011, 286:4727-4741.
56. Cohen A, Ross L, Nachman I, Bar-Nun S: Aggregation of polyQ proteins is increased upon yeast aging and affected by Sir2 and Hsf1: novel quantitative biochemical and microscopic assays. PLoS One 2012, 7:e44785.
57. Rodriguez-Muela N, Boya P: Axonal damage, autophagy and neuronal survival. Autophagy 2012, 8:286-288.
58. Son JH, Shim JH, Kim KH, Ha JY, Han JY: Neuronal autophagy and neurodegenerative diseases. Exp Mol Med 2012, 44:89-98.
59. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC: Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 2007, 282:5641-5652.
60. Yang ZJ, Chee CE, Huang S, Sinicrope FA: The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 2011, 10:1533-1541.
61. Hung CM, Garcia-Haro L, Sparks CA, Guertin DA: mTOR-dependent cell survival mechanisms. Cold Spring Harb Perspect Biol 2012, 4.
62. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B: JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 2008, 30:678-688.
63. Wei Y, Sinha S, Levine B: Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy 2008, 4:949-951.
64. Tu QQ, Zheng RY, Li J, Hu L, Chang YX, Li L, Li MH, Wang RY, Huang DD, Wu MC, et al: Palmitic acid induces autophagy in hepatocytes via JNK2 activation. Acta Pharmacol Sin 2014, 35:504-512.
65. Raciti M, Lotti LV, Valia S, Pulcinelli FM, Di Renzo L: JNK2 is activated during ER stress and promotes cell survival. Cell Death Dis 2012, 3:e429.
66. Zhao T, Hong Y, Li XJ, Li SH: Subcellular Clearance and Accumulation of Huntington Disease Protein: A Mini-Review. Front Mol Neurosci 2016, 9:27.
67. Dong W, Wang R: [Effects of resveratrol-induced cellular autophagy in control of neurodegenerative diseases]. Yao Xue Xue Bao 2016, 51:18-22.
68. Towers CG, Thorburn A: Therapeutic Targeting of Autophagy. EBioMedicine 2016.
69. Johansen T, Lamark T: Selective autophagy mediated by autophagic adapter proteins. Autophagy 2011, 7:279-296.
70. Zhang H, Wu F, Wang X, Du H, Wang X, Zhang H: The two C. elegans ATG-16 homologs have partially redundant functions in the basal autophagy pathway. Autophagy 2013, 9:1965-1974.
71. Wang BY, Huang JY, Cheng CY, Lin CH, Ko J, Liaw YP: Lung cancer and prognosis in taiwan: a population-based cancer registry. J Thorac Oncol 2013, 8:1128-1135.
72. Ridge CA, McErlean AM, Ginsberg MS: Epidemiology of lung cancer. Semin Intervent Radiol 2013, 30:93-98.
73. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA: Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008, 83:584-594.
74. Huang JY, Jian ZH, Nfor ON, Ku WY, Ko PC, Lung CC, Ho CC, Pan HH, Huang CY, Liang YC, Liaw YP: The effects of pulmonary diseases on histologic types of lung cancer in both sexes: a population-based study in Taiwan. BMC Cancer 2015, 15:834.
75. Yu Y, Liu H, Zheng S, Ding Z, Chen Z, Jin W, Wang L, Wang Z, Fei Y, Zhang S, et al: Gender susceptibility for cigarette smoking-attributable lung cancer: a systematic review and meta-analysis. Lung Cancer 2014, 85:351-360.
76. Tota JE, Ramanakumar AV, Franco EL: Lung cancer screening: review and performance comparison under different risk scenarios. Lung 2014, 192:55-63.
77. Tian Y, Liu Q, He X, Yuan X, Chen Y, Chu Q, Wu K: Emerging roles of Nrf2 signal in non-small cell lung cancer. J Hematol Oncol 2016, 9:14.
78. Xu W, Ying Y, Shan L, Feng J, Zhang S, Gao Y, Xu X, Yao Y, Zhu C, Mao W: Enhanced expression of cohesin loading factor NIPBL confers poor prognosis and chemotherapy resistance in non-small cell lung cancer. J Transl Med 2015, 13:153.
79. Yadav P, Lal K, Kumar A, Guru SK, Jaglan S, Bhushan S: Green synthesis and anticancer potential of chalcone linked-1,2,3-triazoles. Eur J Med Chem 2016, 126:944-953.
80. Milosev MZ, Jakovljevic K, Joksovic MD, Stanojkovic T, Matic IZ, Perovic M, Tesic V, Kanazir S, Mladenovic M, Rodic MV, et al: Mannich Bases of 1,2,4-Triazole-3-thione Containing Adamantane Moiety: Synthesis, Preliminary Anticancer Evaluation, and Molecular Modeling Studies. Chem Biol Drug Des 2016.
81. Riedl CA, Flocke LS, Hejl M, Roller A, Klose MH, Jakupec MA, Kandioller W, Keppler BK: Introducing the 4-Phenyl-1,2,3-Triazole Moiety as a Versatile Scaffold for the Development of Cytotoxic Ruthenium(II) and Osmium(II) Arene Cyclometalates. Inorg Chem 2017, 56:528-541.
82. Park K, Lee HE, Lee SH, Lee D, Lee T, Lee YM: Molecular and functional evaluation of a novel HIF inhibitor, benzopyranyl 1,2,3-triazole compound. Oncotarget 2016.
83. Liu R, Li J, Zhang T, Zou L, Chen Y, Wang K, Lei Y, Yuan K, Li Y, Lan J, et al: Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking. Autophagy 2014, 10:1241-1255.
84. Hamidullah, Saini KS, Ajay A, Devender N, Bhattacharjee A, Das S, Dwivedi S, Gupt MP, Bora HK, Mitra K, et al: Triazole analog 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4-bromophenylamino)-1-(4 -chlorophenyl)ethanol induces reactive oxygen species and autophagy-dependent apoptosis in both in vitro and in vivo breast cancer models. Int J Biochem Cell Biol 2015, 65:275-287.
85. Elmore S: Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol 2007, 35:495-516.
86. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, Bao JK: Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 2012, 45:487-498.
87. Chaabane W, User SD, El-Gazzah M, Jaksik R, Sajjadi E, Rzeszowska-Wolny J, Los MJ: Autophagy, apoptosis, mitoptosis and necrosis: interdependence between those pathways and effects on cancer. Arch Immunol Ther Exp (Warsz) 2013, 61:43-58.
88. Reyjal J, Cormier K, Turcotte S: Autophagy and cell death to target cancer cells: exploiting synthetic lethality as cancer therapies. Adv Exp Med Biol 2014, 772:167-188.
89. Ke B, Tian M, Li J, Liu B, He G: Targeting Programmed Cell Death Using Small-Molecule Compounds to Improve Potential Cancer Therapy. Med Res Rev 2016, 36:983-1035.
90. Rao S, Yang H, Penninger JM, Kroemer G: Autophagy in non-small cell lung carcinogenesis: A positive regulator of antitumor immunosurveillance. Autophagy 2014, 10:529-531.
91. Saleh T, Cuttino L, Gewirtz DA: Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer. Biochim Biophys Acta 2016, 1860:2130-2136.
92. Liu LZ, Zhou XD, Qian G, Shi X, Fang J, Jiang BH: AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Cancer Res 2007, 67:6325-6332.
93. Musumeci G, Castrogiovanni P, Trovato FM, Weinberg AM, Al-Wasiyah MK, Alqahtani MH, Mobasheri A: Biomarkers of Chondrocyte Apoptosis and Autophagy in Osteoarthritis. Int J Mol Sci 2015, 16:20560-20575.
94. Hector S, Prehn JH: Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: a review. Biochim Biophys Acta 2009, 1795:117-129.
95. Ganley IG, Wong PM, Gammoh N, Jiang X: Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol Cell 2011, 42:731-743.
96. Liu Y, Zhao L, Ma W, Cao X, Chen H, Feng D, Liang J, Yin K, Jiang X: The Blockage of KCa3.1 Channel Inhibited Proliferation, Migration and Promoted Apoptosis of Human Hepatocellular Carcinoma Cells. J Cancer 2015, 6:643-651.
97. Xie J, Liu JH, Liu H, Liao XZ, Chen Y, Lin MG, Gu YY, Liu TL, Wang DM, Ge H, Mo SL: Tanshinone IIA combined with adriamycin inhibited malignant biological behaviors of NSCLC A549 cell line in a synergistic way. BMC Cancer 2016, 16:899.
98. Li X, Xu HL, Liu YX, An N, Zhao S, Bao JK: Autophagy modulation as a target for anticancer drug discovery. Acta Pharmacol Sin 2013, 34:612-624.
99. Takeuchi H, Kondo Y, Fujiwara K, Kanzawa T, Aoki H, Mills GB, Kondo S: Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 2005, 65:3336-3346.
100. Yoo SH, Yoon YG, Lee JS, Song YS, Oh JS, Park BS, Kwon TK, Park C, Choi YH, Yoo YH: Etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells. Int J Oncol 2012, 41:1443-1454.
101. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P, et al: AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010, 70:288-298.
102. Strahan JA, Walker WH, 2nd, Montgomery TR, Forger NG: Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain. Dev Neurobiol 2016.
103. Azad MB, Chen Y, Gibson SB: Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Signal 2009, 11:777-790.
104. Eng CH, Abraham RT: The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming. Oncogene 2011, 30:4687-4696.
105. Scherz-Shouval R, Elazar Z: Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 2011, 36:30-38.
106. Al Dhaheri Y, Attoub S, Ramadan G, Arafat K, Bajbouj K, Karuvantevida N, AbuQamar S, Eid A, Iratni R: Carnosol induces ROS-mediated beclin1-independent autophagy and apoptosis in triple negative breast cancer. PLoS One 2014, 9:e109630.
107. Zhou ZW, Li XX, He ZX, Pan ST, Yang Y, Zhang X, Chow K, Yang T, Qiu JX, Zhou Q, et al: Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells. Drug Des Devel Ther 2015, 9:1511-1554.
108. Rah B, ur Rasool R, Nayak D, Yousuf SK, Mukherjee D, Kumar LD, Goswami A: PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells. Autophagy 2015, 11:314-331.
109. Zhang W, Zhou H, Yu Y, Li J, Li H, Jiang D, Chen Z, Yang D, Xu Z, Yu Z: Combination of gambogic acid with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression. Onco Targets Ther 2016, 9:3359-3368.
110. Tsujimoto Y, Shimizu S: Another way to die: autophagic programmed cell death. Cell Death Differ 2005, 12 Suppl 2:1528-1534.
111. Maiese K: Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res 2016, 11:372-385.

簡易檢索 / 詳目顯示

相關論文