1. NCHU Institution Repository
  2. 農業暨自然資源學院
  3. 生物科技學研究所
Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/36300
DC FieldValueLanguage
dc.contributor林仁混zh_TW
dc.contributorJen-Kun Linen_US
dc.contributor楊寧蓀zh_TW
dc.contributor陳瑞華zh_TW
dc.contributor陳玉如zh_TW
dc.contributor王升陽zh_TW
dc.contributor吳永昌zh_TW
dc.contributorNing-Sun Yangen_US
dc.contributorRuey-Hwa Chenen_US
dc.contributorYu-Ju Chenen_US
dc.contributorSheng-Yang Wangen_US
dc.contributorYang-Chang Wuen_US
dc.contributor.advisor徐麗芬zh_TW
dc.contributor.advisorLie-Fen Shyuren_US
dc.contributor.author李慧玲zh_TW
dc.contributor.authorLee, Wai-Lengen_US
dc.contributor.other中興大學zh_TW
dc.date2012zh_TW
dc.date.accessioned2014-06-06T07:54:30Z-
dc.date.available2014-06-06T07:54:30Z-
dc.identifierU0005-2507201122485600zh_TW
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dc.identifier.urihttp://hdl.handle.net/11455/36300-
dc.description.abstract越來越多研究指出植物衍生而來的化合物具有化學預防或化學治療的特性，並具有潛能結合現有的化學療法來有效的治療各種癌症。從傳統藥草菊科植物地膽草 (Elephantopus scaber L.) 所萃取出具有抗癌性質的活性成分，主要是屬於倍半萜類 (germacranolid sesquiterpene lactone) 的deoxyelephantopin (DET)。相較於常被使用來治療乳癌的化療藥物紫杉醇 (paclitaxel, PTX)，我們實驗室先前的研究證實不論是在活體外 (in vitro) 或活體內 (in vivo) 的實驗系統下，DET的處理可以更有效的抑制老鼠TS/A乳腺腫瘤的生長與轉移。本論文研究主要利用蛋白質體技術也就是二維凝膠電泳及液相層析-電熱灑離子化二次質譜儀 (liquid chromatography electrospray ionization tandem mass spectrometry, LC-ESI-MS/MS) 來分析TS/A細胞中蛋白質在DET 和PTX的處理下表現的差異，然後利用生物資訊軟體MetaCore來分析顯示差異的蛋白之間的相互關係以及有關的生物訊息途徑。實驗結果顯示，DET和PTX對涉及蛋白質降解及鈣離子傳送的蛋白質有顯著的影響，從而推斷出這兩種化合物可能會影響TS/A細胞中蛋白酶體 (proteasome) 及內質網的功能。利用西方墨點法進一步證實，DET和PTX的處理同樣會引起內質網的壓力 (ER stress) 繼而導致細胞凋亡，而只有DET可以抑制TS/A細胞蛋白酶體中蛋白質降解的功能。另一方面，蛋白質體研究的結果也顯示DET會影響TS/A細胞的肌動蛋白 (actin) 系統，同時抑制鈣蛋白酵素 (calpain) 對多種骨架蛋白質的水解，而PTX主要是影響細胞內微管蛋白質系統。在更深入的實驗中發現DET會影響鈣蛋白酵素的催化活性及其所調控的細胞運動形態。MetaCore分析的結果也顯示Rho GTPase可能涉及DET對肌動蛋白的作用，而DET對TS/A細胞的處理確實明顯的抑制了由上皮生長因子 (EGF) 活化的Rac 1蛋白及其下游的層狀偽足 (lamellipodia) 的形成。另外，DET會阻擾上皮生長因子在TS/A細胞中的運輸及導致被泛素修飾的蛋白 (ubiquitinated proteins) 聚集在中心體所在處。值得注意的是，DET所誘導產生的活性氧化物 (ROS) 是引發中心體聚集物的上游刺激分子，進而可能造成限制乳癌細胞的活性及移動能力。綜合以上結果，本篇論文之研究提供深入證據闡明DET抑制乳腺癌細胞的活性與轉移的新穎藥理作用機制。zh_TW
dc.description.abstractAccumulating evidences have shown that various plant-derived phytocompounds possess chemopreventive or chemotherapeutic properties, suggesting their potential for use in combination with chemotherapeutics as effective treatments for various cancers. One such potent antitumor phytocompound is the major germacranolide sesquiterpene lactone, deoxyelephantopin (DET) from the traditional medicinal herb Elephantopus scaber L (Asteraceae). Previously, DET was found in our lab to suppress mammary carcinoma metastasis in vitro and in vivo with a more superior effect than Paclitaxel (PTX), a front line chemotherapeutic agent commonly utilized in the treatment of breast cancer. In this study, two-dimensional differential in-gel electrophoresis (2-D DIGE) and liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) were first used to profile proteins differentially expressed in TS/A cells, and affected functional protein networks were analyzed using MetaCore database. DET and PTX treatment resulted in regulation of molecules involved in proteolysis and calcium ion transport, suggesting the possible effects of both chemicals on proteasome and endoplasmic reticulum (ER) machinery in TS/A cells. Western blot analysis of marker proteins further verified that induction of ER stress was associated with apoptosis induced by both DET and PTX, but only DET inhibited proteasomal proteolysis in TS/A cells. Besides, proteomic study also suggested that DET affects actin cytoskeletal protein networks and downregulates calpain proteolyzed fragments of several actin-associated proteins, while PTX interferes mainly with microtubule proteins. Further investigation of the putative inhibitory effect of DET on calpain and associated cytoskeletal regulation found that DET inhibits enzymatic activity of calpain in TS/A cells. As Rho GTPases were suggested as part of DET action by MetaCore network analysis, epithelial growth factor (EGF)-mediated activation of Rac1 and formation of lamellipodia in TS/A cells were indeed remarkably suppressed by DET treatment. Further, DET impaired vesicular trafficking of EGF and induced formation of centrosomal aggregates of ubiquitinated proteins in TS/A cells. Notably, DET-induced reactive oxygen species (ROS) was observed to be the trigger for inducing the centrosomal ubiquitinated protein aggregates that might subsequently restrict cancer cell viability and motility. Together, this study provides novel mechanistic insights into the pharmacological action of DET against metastatic mammary cell migration.en_US
dc.description.tableofcontentsTable of contents..................................... i List of Figures....................................... vii List of Tables........................................ ix Abbreviations......................................... x Abstract (Chinese).................................... xv Abstract (English).................................... xvi Part 1. Introduction of phytoagent deoxyelephantopin and its potential development in therapeutic intervention of breast cancer................................................ 1 1.1 Breast cancer treatment approaches and barriers 2 1.2 Research of phytoagents in cancer treatment... 4 1.3 Deoxyelephantopin (DET)....................... 5 1.4 Research design and experiment approaches..... 8 Part 2. Differential proteomic profiling identifies novel molecular targets of phytoagent deoxyelephantopin and clinical drug paclitaxel against mammary adenocarcinoma cells................................................. 11 2.1 Introduction.................................. 12 2.1.1 DIGE in 2-DE proteomics study................. 12 2.1.2 Bioinformatic data mining and target discovery 13 2.2 Materials and Methods......................... 15 2.2.1 Isolation and structure elucidation of DET.... 15 2.2.2 Chemicals & Reagents.......................... 15 2.2.3 Cell culture.................................. 16 2.2.4 Cytotoxicity assay............................ 16 2.2.5 Nuclear and cytoplasmic protein extraction.... 16 2.2.6 DIGE experimental design...................... 17 2.2.7 DIGE 2-DE..................................... 17 2.2.8 DIGE image analysis........................... 18 2.2.9 In-gel trypsin digestion...................... 18 2.2.10 MS analysis and protein identification....... 19 2.2.11 Database search.............................. 19 2.2.12 Bioinformatics analysis...................... 20 2.2.13 Western blotting............................. 20 2.2.14 Assay for proteasome activities.............. 21 2.2.15 Immunofluorescence and microscopy............ 21 2.2.16 Statistical analysis......................... 22 2.3 Results....................................... 22 2.3.1 Cytotoxic effects of DET and PTX in mammary carcinoma cells....................................... 22 2.3.2 2-DE analysis of vehicle control, DET and PTX treated mammary carcinoma cells....................... 22 2.3.3 Identification of the differentially expressed proteins.............................................. 23 2.3.4 Protein database search and classification.... 24 2.3.5 Bioinformatic analysis of subcellular treatment responsive protein networks........................... 24 2.3.6 Bioinformatic analysis of time course dependent treatment responsive protein networks................. 25 2.3.7 Regulation of proteasome and ER associated proteins in treated TS/A cells................................. 26 2.3.8 Regulation of ubiquitin proteasome mediated proteolysis in treated TS/A cells..................... 27 2.3.9 Induction of cell stress and programmed cell death in DET and PTX-treated cells.......................... 28 2.4 Discussion.................................... 29 2.4.1 Cell cycle and DNA damage..................... 30 2.4.2 Heterogeneous nuclear ribonucleoproteins...... 30 2.4.3 Enzymes in response to DET-treated TS/A cells. 31 2.4.4 Ubiquitin proteasome proteolysis in DET-treated TS/A cells................................................. 31 2.4.5 ER stress and apoptosis induction in DET-treated TS/A cells............................................ 32 2.4.6 Regulations in response to PTX treatment...... 33 Part 3. Deoxyelephantopin impedes mammary adenocarcinoma cell motility through inhibiting calpain-mediated adhesion dynamics and inducing ROS and aggresome formation..... 55 3.1 Introduction.................................. 56 3.1.1 Rho-family GTPases............................ 56 3.1.2 Calpain and tumor malignancy.................. 57 3.1.3 Reactive oxygen species (ROS) and cancer...... 58 3.2 Materials and Methods......................... 59 3.2.1 Cell lines and cell cultures.................. 59 3.2.2 Isolation and structure elucidation of DET.... 59 3.2.3 Chemicals and reagents........................ 59 3.2.4 Timelapse microscopy.......................... 60 3.2.5 Immunofluorescence cell staining.............. 60 3.2.6 Fluorescence imaging.......................... 61 3.2.7 In vitro calpain cleavage assay............... 61 3.2.8 BOC assay..................................... 61 3.2.9 Spreading assay............................... 62 3.2.10 Migration assay.............................. 62 3.2.11 Rho GTPases activation assay................. 62 3.2.12 Measurement of ROS........................... 63 3.2.13 Western blotting............................. 63 3.2.14 Immunoprecipitation.......................... 63 3.2.15 Statistical analysis......................... 64 3.3 Results....................................... 64 3.3.1 Proliferation and migration kinetics of TS/A cells treated with DET and PTX.............................. 64 3.3.2 Regulation of actin and the microtubule cytoskeleton.......................................... 65 3.3.3 Inhibition of proteolysis of actin cytoskeleton-associated proteins by DET identified by differential proteomic profiling................................... 66 3.3.4 Inhibition of calpain activity and FAK proteolysis........................................... 67 3.3.5 Effect of DET on formation of focal adhesions 68 3.3.6 Effect of DET on cell membrane protrusion... 68 3.3.7 Effect of DET on Rho GTPases activation and lamellipodia formation................................ 69 3.3.8 Deregulation of EGF delivery and formation of centrasomal aggregates................................ 70 3.3.9 Effect of DET-induced ROS on centrosomal aggregation and ubiquitinated protein accumulation.... 71 3.3.10 Effect of DET-induced ROS on TS/A cell viability and cell migration.................................... 72 3.4 Discussion.................................... 73 3.4.1 Calpain system in DET-treated TS/A cells...... 73 3.4.2 Membrane protrusion in DET-treated TS/A cells. 74 3.4.3 ROS-induced aggresome formation and apoptosis in DET-treated TS/A cells................................ 75 3.4.4 Cytoskeletal regulations in DET-treated TS/A cells................................................. 76 3.4.5 Regulations in PTX-treated TS/A cells......... 77 Part 4. Conclusions and future prospects.............. 97 4.1 Conclusions................................... 98 4.2 Future prospects.............................. 101 References............................................ 107 Appendix.............................................. 121 Supplementary Fig. 2-1. Preliminary 2-DE image analysis 122 Supplementary Fig. 2-2. Verification of TS/A cell fractionation......................................... 122 Supplementary Fig. 2-3. DIGE image analysis using DeCyder differential analysis module.......................... 123 Supplementary Fig. 3-1. Desensitization of GPCR protein signaling pathway..................................... 124 Supplementary Table 2-1. Number of detected protein spots with significant relative fold change (>1.5) in DET- and PTX-treated TS/A cells (P < 0.05)..................... 125 Supplementary Methods. MetaCore database architecture. 125 Curriculum vitae...................................... 130 List of Figures Fig. 1-1. Chemical structures of sesquiterpene lactones 6 Fig. 1-2. Schematic flow chart of research design and experimental procedures............................... 10 Fig. 2-1. Effect of DET and PTX on TS/A cell viability 42 Fig. 2-2. Experimental design and protocol of 2-DE DIGE 43 Fig. 2-3. Proteome maps with indicated DET and PTX responsive proteins inTS/A cells...................... 44 Fig. 2-4. Functional classification of DET and PTX responsive proteins................................... 46 Fig. 2-5. Time-course dependent regulation of protein networks responsive to DET and PTX treatment.......... 47 Fig. 2-6. Proteasome and ER-associated proteins....... 48 Fig. 2-7. Regulation of ubiquitin proteasome proteolysis inTS/A cells.......................................... 50 Fig. 2-8. Induced cell stress responses and programmed cell death in treated TS/A cells........................... 52 Fig. 2-9. Proposed molecular mechanism of DET and PTX-induced programmed cell death in TS/A mammary adenocarcinoma cells................................................. 54 Fig. 3-1. Kinetic characteristics of the migration of TS/A cells treated with DET and PTX........................ 79 Fig. 3-2. Immunofluorescence analysis of actin and microtubule organization in DET-and PTX- treated TS/A cells. 81 Fig. 3-3. Cytoskeleton-associated proteins with inhibited proteolysis identified from differential proteomic profiling of DET treated TS/A cells............................. 82 Fig. 3-4. Effect of calpain activity in TS/A cells.... 84 Fig. 3-5. Effect on formation of focal adhesion in TS/A cells................................................. 86 Fig. 3-6. Effect of cell spreading and lamellipodia formation in TS/A cells............................... 88 Fig. 3-7. Deregulation of EGF delivery and formation of centrasomal aggregates................................ 90 Fig. 3-8. Effect of ROS on centrosomal aggregation and ubiquitinated protein accumulation.................... 92 Fig. 3-9. Effect of ROS on TS/A cell viability and cell migration............................................. 94 Fig. 3-10. Summary of proposed molecular mechanisms underlying inhibitory effect of DET in suppression of TS/A cell migration........................................ 96 Fig. 4-1. Summary of putative protein networks involved in DET- and PTX-mediated suppression on TS/A mammary carcinoma cell activities....................................... 105 List of Tables Table 2-1. Identification of differentially expressed proteins in DET-treated TS/A cells.................... 35 Table 2-2. Identification of differentially expressed proteins in PTX-treated TS/A cells.................... 38 Table 2-3. MetaCore network analysis of DET modulated protein networks in TS/A cells........................ 40 Table 2-4. MetaCore network analysis of PTX modulated protein networks in TS/A cells........................ 41en_US
dc.language.isoen_USzh_TW
dc.publisher生物科技學研究所zh_TW
dc.relation.urihttp://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2507201122485600en_US
dc.subject倍半萜類zh_TW
dc.subjectpharmacological actionen_US
dc.subject傳統藥草zh_TW
dc.subject地膽草zh_TW
dc.subject紫杉醇zh_TW
dc.subject乳腺腫瘤zh_TW
dc.subject活性氧化物zh_TW
dc.subject中心體zh_TW
dc.subject泛素zh_TW
dc.subject上皮生長因子zh_TW
dc.subject細胞運動zh_TW
dc.subject微管蛋白質zh_TW
dc.subject骨架蛋白質zh_TW
dc.subject鈣蛋白酵素zh_TW
dc.subject肌動蛋白zh_TW
dc.subject細胞凋亡zh_TW
dc.subject內質網zh_TW
dc.subject二維凝膠電泳zh_TW
dc.subject蛋白酶體zh_TW
dc.subject蛋白質體zh_TW
dc.subject轉移zh_TW
dc.subject藥理作用機制zh_TW
dc.subject乳癌治療zh_TW
dc.subjectcell motilityen_US
dc.subjectreactive oxygen speciesen_US
dc.subjectubiquitinated proteinsen_US
dc.subjectcentrosomal aggregatesen_US
dc.subjectepithelial growth factoren_US
dc.subjectcalpainen_US
dc.subjectcytoskeletal proteinen_US
dc.subjectactinen_US
dc.subjectproteomic studyen_US
dc.subjectproteasomal proteolysisen_US
dc.subjectapoptosisen_US
dc.subjectendoplasmic reticulum stressen_US
dc.subjectproteasomeen_US
dc.subjectMetaCore databaseen_US
dc.subjecttwo-dimensional differential in-gel electrophoresisen_US
dc.subjectbreast cancer treatmenten_US
dc.subjecttraditional medicinal herben_US
dc.subjectElephantopus scaberen_US
dc.subjectgermacranolide sesquiterpene lactoneen_US
dc.subjectdeoxyelephantopinen_US
dc.subjectpaclitaxelen_US
dc.subjectTS/A cellsen_US
dc.subjectmammary adenocarcinomaen_US
dc.subjectmetastasisen_US
dc.title植物成分deoxyelephantopin與化療藥紫杉醇作用於乳腺癌細胞之分子標的與機制研究zh_TW
dc.titleNovel molecular targets and mechanisms of phytoagent deoxyelephantopin and chemotherapeutic drug paclitaxel against mammary carcinoma cellen_US
dc.typeThesis and Dissertationzh_TW
item.openairetypeThesis and Dissertation-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.languageiso639-1en_US-
item.grantfulltextnone-
item.fulltextno fulltext-
item.cerifentitytypePublications-
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