請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/98567完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 阮雪芬 | zh_TW |
| dc.contributor.advisor | Hsueh-Fen Juan | en |
| dc.contributor.author | 游佩蓁 | zh_TW |
| dc.contributor.author | Pei-Chen Yu | en |
| dc.date.accessioned | 2025-08-18T00:54:25Z | - |
| dc.date.available | 2025-08-18 | - |
| dc.date.copyright | 2025-08-15 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-08-06 | - |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/98567 | - |
| dc.description.abstract | 神經母細胞瘤為常見且高度惡性的兒童腫瘤，目前仍缺乏有效治療策略。近年來，「藥物重新定位」被視為解決此臨床缺口的有望途徑。本研究使用 LINCS (Library of Integrated Network-Based Cellular Signatures)資料庫中的小分子誘導基因表現譜，系統性鑑定出兩種已獲 FDA 核准的藥物pyrvinium pamoate 及 sirolimus作為潛在的合併用藥組合。功能性試驗（集落形成以及三維病人來源類器官模型）顯示，雙藥併用相較於單獨施用任一藥物，具有顯著提升的抗腫瘤效力。由 LINCS 分析預測的多個靶基因在藥物處理後樣本中同步下調。為闡明協同效應的機制，我們採用 TMT (Tandem Mass Tag) 串聯質譜標籤進行定量蛋白體學的分析，於 20,623 條胜肽序列中鑑定出 3,416 種蛋白質。接著透過 GSEA 與 DAVID 生物資訊平台進行路徑分析，結果顯示合併用藥可大幅抑制細胞骨架形成，與觀察到的細胞遷移能力降低相符；同時，蛋白質表現譜亦指出合併用藥導致明顯的細胞週期停滯。進一步實驗證實，在雙藥併用條件下自噬活性顯著升高。
總結而言，本研究揭示了pyrvinium pamoate 及 sirolimus併用提升療效的分子機制，並支持其作為低毒性、可重新定位之藥物組合，用於改善神經母細胞瘤治療成果的潛力。 | zh_TW |
| dc.description.abstract | Neuroblastoma is a common and highly malignant pediatric tumor that currently lacks effective therapeutic strategies. Drug repurposing has recently emerged as a promising avenue to address this unmet clinical need. In this study, we systematically screened small-molecule-induced gene expression profiles from the Library of Integrated Network-Based Cellular Signatures (LINCS) and identified two FDA-approved compounds pyrvinium pamoate and sirolimus as promising candidates for combinatorial therapy against neuroblastoma. Functional assays, including colony formation and three-dimensional patient-derived organoid models, demonstrated that the combined application of these two agents produced significantly greater antitumor efficacy than either compound used individually. Expression levels of multiple target genes predicted through LINCS analysis were concurrently downregulated in treated samples. To elucidate the underlying mechanisms responsible for this enhanced efficacy, we employed tandem mass tag (TMT)-based quantitative proteomic profiling, identifying 3,416 proteins across 20,623 peptide sequences. Subsequent pathway analysis using Gene Set Enrichment Analysis (GSEA) and the DAVID bioinformatics resource revealed that the combination therapy led to a marked suppression of cytoskeletal assembly, which was consistent with the observed inhibition of cellular motility. In addition, protein expression profiles indicated that the dual-drug treatment resulted in significant cell cycle arrest. Further investigations confirmed that autophagic activity was notably elevated under combination treatment conditions. Collectively, these findings provide mechanistic insight into the enhanced therapeutic action of sirolimus and pyrvinium pamoate co-administration and support their potential use as a low-toxicity, repurposed drug combination for improving neuroblastoma treatment outcomes. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-08-18T00:54:25Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-08-18T00:54:25Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 目次
口試委員審定書……………………………………………………………………….i 致謝……………………………………………………………………………………ii 中文摘要…………………………………………………………………………iii Abstract…………………………………………………………………………… iv 目次.................................................................................................................vi List of Figures....................................................................................................................x List of Tables....................................................................................................................xii List of Appendix..... ........................................................................................................ xiv Chapter 1. Introduction.......................................................................................................1 1.1 Overview of neuroblastoma..................................................................................1 1.2 Molecular heterogeneity of neuroblastoma.........................................................11 1.3 Transcriptomic subtypes: ADRN vs MES..........................................................22 1.4 Tumor microenvironment and immune evasion...................................................2 1.5 Evolution of clinical staging.................................................................................3 1.6 Limitations and challenges of current therapies...................................................4 1.7 Drug repurposing and combination therapy strategies.........................................4 1.8 High-throughput drug screening...........................................................................5 1.9 Sirolimus: targeting the mTOR pathway...............................................................6 1.10 Pyrvinium pamoate: inhibiting WNT signaling and mitochondrial function.......7 1.11 Proteomic evaluation of combination efficacy.....................................................8 1.12 Objective of thesis................................................................................................8 Chapter 2. Materials and Methods..................................................................................10 2.1 Cell lines ...............................................................................................................10 2.2 Cell viability assay..............................................................................................10 2.3 Colony forming assay ........................................................................................11 2.4 Drug response quantification and synergy analysis.............................................11 2.5 Patient material processing..................................................................................12 2.6 Isolation of specimen cells ...................................................................................14 2.7 3D organoid formation and maintenance.............................................................15 2.8 Effects of drug treatment on survival of 3d organoids.........................................15 2.9 Cell synchronization.............................................................................................16 2.10 Immunofluorescence..........................................................................................17 2.11 Real-time PCR....................................................................................................19 2.12 Sample preparation for quantitative proteome analysis......................................21 2.13 Nano lc–ms/ms and data analysis.......................................................................22 2.14 Principal component analysis.............................................................................24 2.15 Functional enrichment with gene ontology analysis..........................................24 2.16 Gene set enrichment analysis.............................................................................25 2.17 Cell migration assay...........................................................................................25 2.18 Western blotting.................................................................................................26 2.19 Statistical analysis..............................................................................................27 Chapter 3. Result..............................................................................................................28 3.1 Combination treatment of sirolimus and pyrvinium pamoate decreased the proliferation of neuroblastoma............................28 3.2 Gene expression and pathway analysis unveiling the possible mechanisms of combination treatment of sirolimus and pyrvinium pamoate..............30 3.3 Quantitative proteomic analysis reveals the impact of combination therapy.......31 3.4 Functional enrichment analysis revealed the molecular mechanisms of dual-drug treatment......................................33 3.5 Combination therapy induced cell migration and cell death through autophagy.......................................... 35 Chapter 4. Discussion......................................................................................................38 Chapter 5. Conclusion.....................................................................................................50 References........................................................................................................................52 Figures..............................................................................................................................77 Tables..............................................................................................................................101 Appendix........................................................................................................................147 List of Figures Fig. 1. Evaluation of neuroblastoma cell line responses to sirolimus and pyrvinium pamoate combination treatment...................................................77 Fig. 2. Correlation of genes affected by pyrvinium pamoate and sirolimus with prognostic overall survival in neuroblastoma...........................79 Fig. 3. Effect of pyrvinium pamoate and sirolimus on mRNA expression in neuroblastoma cell lines...83 Fig. 4. The 12 genes suppressed by pyrvinium pamoate and sirolimus treatment impair mitotic progression in neuroblastoma cells.................................................85 Fig. 5. Representative images and quantification of mitotic cell ratios....................................................87 Fig. 6. Experimental design for quantitative proteomic analysis of SK-N-DZ cells after treatment with pyrvinium pamoate, sirolimus, or the combination of both............89 Fig. 7. Quantitative proteomic profiling of SK-N-DZ cells following treatment with pyrvinium pamoate, sirolimus, or their combination......................90 Fig. 8. Biological process alterations induced by monotherapy and combination treatment...................92 Fig. 9. DAVID functional annotation highlights differential biological effects of pyrvinium pamoate, sirolimus, and their combination in SK-N-DZ cells.......94 Fig. 10. Combined treatment disrupts cytoskeletal organization.............................................................96 Fig. 11. Combination therapy induces autophagy-mediated cell death in SK-N-DZ cells.......................98 Fig. 12. Western blot original images...............................100 List of Tables Table 1: Predicted impact of combined therapy in neuroblastoma cell lines...........................................101 Table 2: Up regulated proteins for quantitative proteomics of treatment with pyrvinium pamoate, sirolimus or combination therapy in SK-N-DZ........................................102 Table 3: Down regulated proteins for quantitative proteomics of treatment with pyrvinium pamoate, sirolimus or combination therapy in SK-N-DZ.........................................112 Table 4: The DAVID analysis revealed significant differences between pyrvinium pamoate treated and control-treated SK-N-DZ cells..............................123 Table 5: The GSEA revealed significant differences between pyrvinium pamoate-treated and control-treated SK-N-DZ cells........................................129 Table 6: The DAVID analysis revealed significant differences between sirolimus-treated and control-treated SK-N-DZ cells..........................131 Table 7: The GSEA revealed significant differences between sirolimus-treated and control-treated SK-N-DZ cells..................................................................132 Table 8: The DAVID analysis revealed significant differences between combine-treated and control-treated SK-N-DZ cells from batch1....134 Table 9: The DAVID analysis revealed significant differences between combine-treated and control-treated SK-N-DZ cells from batch 2...........................................135 Table 10: The GSEA revealed significant differences between combine-treated and control-treated SK-N-DZ cells from batch 1.................................................137 Table 11: The GSEA revealed significant differences between combine-treated and control-treated SK-N-DZ cells from batch 2.....................................................140 Table 12: The DAVID analysis revealed significant differences between combine-treated and pyrvinium pamoate-treated SK-N-DZ cells..............................................141 Table 13: The DAVID analysis revealed significant differences between combine-treated and sirolimus-treated SK-N-DZ cells.......................................................142 Table 14: The GSEA revealed significant differences between combine-treated and pyrvinium pamoate-treated SK-N-DZ cells.......................................................143 Table 15: The GSEA revealed significant differences between combine-treated and sirolimus-treated SK-N-DZ cells.........................................................144 Appendix Appendix 1. Global proteome profile of control, pyrvinium pamoate, sirolimus and combined treatment for neuroblastoma............................................146 | - |
| dc.language.iso | en | - |
| dc.subject | pyrvinium pamoate | zh_TW |
| dc.subject | 神經母細胞瘤 | zh_TW |
| dc.subject | 合併治療 | zh_TW |
| dc.subject | tandem mass tag | zh_TW |
| dc.subject | sirolimus | zh_TW |
| dc.subject | sirolimus | en |
| dc.subject | tandem mass tag | en |
| dc.subject | combination therapy | en |
| dc.subject | pyrvinium pamoate | en |
| dc.subject | Neuroblastoma | en |
| dc.title | 定量蛋白體學解析合併用藥對神經母細胞瘤細胞骨架組成與自噬誘導細胞死亡的協同效應 | zh_TW |
| dc.title | Quantitative Proteomics Unveils Synergistic Effects of Combination drugs on Cytoskeleton Composition and Autophagy-Mediated Cell Death in Neuroblastoma | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 黃宣誠;張心儀;徐駿森;李岳倫 | zh_TW |
| dc.contributor.oralexamcommittee | Hsuan-Cheng Huang;Hsin-Yi Chang;Chun-Hua Hsu;Alan Yueh-Luen Lee | en |
| dc.subject.keyword | 神經母細胞瘤,pyrvinium pamoate,sirolimus,tandem mass tag,合併治療, | zh_TW |
| dc.subject.keyword | Neuroblastoma,pyrvinium pamoate,sirolimus,tandem mass tag,combination therapy, | en |
| dc.relation.page | 312 | - |
| dc.identifier.doi | 10.6342/NTU202503529 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-08-10 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | - |
| dc.date.embargo-lift | 2025-08-18 | - |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
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