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研究生: 陳晴盈
Chen, Ching-Ying
論文名稱: 透過生物資訊學探討Ferroptosis在人類大腸直腸癌細胞中植化素Withaferin A合併鉑金類抗癌藥物的角色
The role of Ferroptosis in the combination treatment of Withaferin A and platinum anticancer agent in human colorectal cancer cells via bioinformatics analysis
指導教授: 蘇純立
Su, Chun-Li
口試委員: 蘇純立
Su, Chun-Li
黃奇英
Huang, Chi-Ying
劉校生
Liu, Hsiao-Sheng
蕭寧馨
Shaw, Ning-Shin
口試日期: 2024/07/04
學位類別: 碩士
Master
系所名稱: 營養科學碩士學位學程
Graduate Program of Nutrition Science
論文出版年: 2024
畢業學年度: 112
語文別: 中文
論文頁數: 115
中文關鍵詞: Ferroptosis大腸直腸癌CisplatinWithaferin AFerritinophagy
英文關鍵詞: Ferroptosis, Colorectal cancer, Cisplatin, Withaferin A, Ferritinophagy
研究方法: 實驗設計法
DOI URL: http://doi.org/10.6345/NTNU202401461
論文種類: 學術論文
相關次數: 點閱:80下載:1
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  • 在大腸直腸癌(Colorectal cancer,CRC)中,鉑金類藥物Cisplatin(Cis)的藥物不敏感與副作用的特性已成為十分嚴重問題。鐵依賴型細胞死亡(Ferroptosis)是透過增加細胞內游離鐵堆積並促進脂質過氧化物生成所導致的新型態細胞死亡機制。透過生物資訊學分析結果發現Cis藥物阻抗的CRC患者體內較藥物敏感的患者具有鐵代謝失調的問題。CRC組織較其他癌症組織有堆積較多二價鐵離子的潛力,並且CRC組織相較於正常組織有累積較多游離鐵與促進脂質過氧化物形成的特性,因此透過二價游離鐵促進細胞活性氧物質生成與降低抗氧化能力來誘導Ferroptosis將有機會改善CRC較低的無復發存活率。此外,相較於HCT116,Ferroptosis促進劑RSL3在HT-29中能引起更高的生長抑制作用,並且可以被Ferroptosis抑制劑Ferrostatin-1和Deferoxamine逆轉細胞生長抑制。同時HT-29中有較低的出鐵蛋白表現,代表細胞中可透過增加細胞內游離鐵來促進Ferroptosis。生物資訊學分析結果發現南非醉茄的酯類成分Withaferin A(WA)具有誘導Ferroptosis的潛力,並且在CRC中WA較Cis有較佳的藥物敏感性。合併Cis與WA能夠促進HT-29進行Ferroptosis相關生長抑制、脂質過氧化物累積、游離鐵累積與降低GPX4蛋白表現。此外,合併Cis與WA能增加shGFP HT-29的細胞生長抑制與促進ferritin與LC3B蛋白共位的情形,而這些結果在加入合併藥物的shATG5 HT-29會被抑制,代表Cis與WA可以增加細胞進行ferrtinophagy。綜合以上結果,本研究利用生物資訊學與實驗數據證實在CRC中植化素WA合併Cis能產生協同作用並促進Ferroptosis。

    Drug resistance and side effect in Cisplatin (Cis) had become a serious problem in colorectal cancer (CRC). Ferroptosis is an iron-dependent regulated cell death caused by toxic lipid peroxidation. Through bioinformatics analysis, we discovered that Cis-resistant CRC patients exhibit iron metabolism disorders compared to the Cis-sensitive patients. Besides, CRC tissues, in contrast to other cancer tissues and normal tissues near by the CRC, tended to accumulate Fe2+ and promote lipid peroxidation. Therefore, inducing ferroptosis by increasing intracellular Fe2+ and reducing antioxidant capacity may improve the low relapse-free survival rate in CRC. Compared to HCT116, ferroptosis inducer RSL3 induced a higher growth inhibition in HT-29, and the growth inhibition was reduced by ferroptosis inhibitor Ferrostatin-1 and Deferoxamine. This observation is associated with a lower ferroportin in HT-29, indicating that increasing labile iron pool can promote Ferroptosis in HT-29. By analyzing the transcriptomics data, natural compound Withaferin A (WA) derived from Withania somnifera has the potential to induce Ferroptosis, and WA exhibits better drug sensitivity in CRC compared to Cis. Combination of Cis and WA-induced Ferroptosis in HT-29 was characterized by increasing growth inhibition and repressing GPX4 protein expression, also increasing lipid peroxides and cellular Fe2+ accumulation. Furthermore, the combination of Cis and WA increased growth inhibition and promoted the colocalization of ferritin and LC3B in shGFP HT-29 cells, while these effects were suppressed in Cis and WA treated shATG 5 HT-29 cells, indicating that Cis and WA enhanced ferritinophagy in HT-29 cells. Collectively, our unique integrated screening results and experimental data support the combination of natural compound WA and Cisplatin in producing synergistic effects and inducing ferroptosis in CRC.

    1. 緒論 1 1.1. 大腸直腸癌 1 1.1.1. 流行病學 1 1.1.2. 大腸直腸癌臨床治療困境 2 1.2. 鐵與癌症 2 1.3. Cisplatin 3 1.4. 鐵依賴型細胞死亡(Ferroptosis) 4 1.4.1. 鐵依賴型細胞死亡機轉 5 1.4.1.1. 游離鐵的增加 5 1.4.1.2. 細胞膜上脂質過氧化物的累積 6 1.4.1.3. 抗氧化能力下降 7 1.4.2. Ferroptosis在大腸直腸癌治療上的潛力 7 1.5. Withaferin A(WA)8 2. 研究目的 10 2.1. 確認大腸直腸癌是否適合作為誘導Ferroptosis的癌症類別,並且挑選出合適的大腸直腸癌細胞株 10 2.2. 透過生物資訊學預測具有誘導大腸直腸癌進行Ferroptosis的植化素 11 2.3. 檢測Cisplatin與WA誘導的大腸直腸癌死亡機制是否與Ferroptosis相關並探討可能的機轉 11 3. 材料與方法 13 3.1. 藥品與試劑 13 3.2. 實驗耗材與儀器 16 3.3. 實驗方法 22 3.3.1. 細胞培養、繼代、解凍與冷凍保存 22 3.3.1.1. 細胞培養與繼代 24 3.3.1.2. 細胞解凍 24 3.3.1.3. 細胞冷凍保存 25 3.3.1.4.細胞計數 25 3.3.2. 藥品配置 26 3.3.2.1. (1S, 3R)-RSL3 (RSL3) 26 3.3.2.2. Deferoxamine mesylate salt 26 3.3.2.3. Ferrostatin-1 (Fer-1) 26 3.3.2.4. Withaferin A (WA) 26 3.3.3. 生物資訊學分析 27 3.3.3.1. Xena 27 3.3.3.2. KM-plotter 27 3.3.3.3. Gene set enrichment analysis (GSEA) 27 3.3.3.4. Dependency Map (DepMap) 27 3.3.3.5. CLUE database、ConsensusPathDB (CPDB) 28 3.3.3.6. NCI-60 28 3.3.4. 細胞存活率 28 3.3.5. 西方墨點法 (Western blotting) 29 3.3.5.1. 細胞蛋白製備 (Preparation of whole cell lysate) 29 3.3.5.2. 蛋白質濃度定量 (Quantitation of protein concentration) 30 3.3.5.3. 聚丙烯醯胺膠體電泳 (SDS-polyacrylamide gel electrophoresis) 31 3.3.5.4. 蛋白質樣品配製(Preparation of protein samples) 34 3.3.5.5. 電泳(Electrophoresis) 34 3.3.5.6. 蛋白質轉漬(Transfer) 35 3.3.5.7. 抗體雜交與顯影(Immunoblotting and imaging) 36 3.3.6. 細胞游離鐵分析 (Labile iron pool analysis) 39 3.3.6.1. FerroOrange 39 3.3.6.2. Phen green SK (PGSK) 40 3.3.7. 脂質過氧化物分析(Lipid peroxidation analysis)41 3.3.8. 免疫螢光染色 (Immunofluorescence,IF) 43 3.3.9. 還原態GSH含量分析 45 3.4. 統計分析 (Statistical analysis) 49 4. 實驗結果 50 4.1. 大腸直腸癌是具有潛力誘導Ferroptosis的癌症類別 50 4.2. HT-29對於RSL3有較佳的敏感性 57 4.3. 大腸直腸癌細胞Ferroptosis相關蛋白表現量的差異 60 4.4. 植化素WA適合誘導大腸直腸癌細胞進行Ferroptosis 63 4.5. 在HT-29中Cisplatin與WA能誘導大腸直腸癌細胞鐵依賴型死亡並促進協同作用 67 4.6. Cisplatin與WA誘導大腸直腸癌細胞二價游離鐵累積 72 4.7. Cisplatin與WA誘導大腸直腸癌細胞脂質過氧化物的生成 76 4.8. HT-29加入Cisplatin與WA後在不同時間點影響Ferroptosis相關蛋白的表現量差異 79 4.9Cisplatin與WA誘導大腸直腸癌細胞進行Ferritinophagy 82 5.討論 90 5.1. 鐵代謝平衡對大腸直腸癌發展的影響 90 5.2. 大腸直腸癌抗癌藥物Cisplatin治療困境與解決方法 93 5.3. 合併植化素WA對Cisplatin治療大腸直腸癌的影響 95 6. 結論 99 7. 參考文獻 100 8. 補充圖次 107 7. 附錄圖次 114

    衛生福利部(2023)‧110年國人死因統計結果‧取自https://www.mohw.gov.tw/cp-16-70314-1.html
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