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研究生(外文):Shuo-Hsuan Hsu
論文名稱:Eupalinolide A抑制小鼠乳癌細胞增生功效之機制
論文名稱(外文):Mechanisms mediating the anti-proliferative effect of eupalinolide A in mammary cancer cells
指導教授(外文):Chi-Chen Lin
外文關鍵詞:Eupaliniolide ABreast cancerCell cycle arrestApoptosisAutophagy
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乳癌已成為世界上最頻繁被診斷出的癌症,在造成死亡的癌症排名中佔第五位。依照乳癌細胞表面受體:雌性激素受體 (Estrogen receptor, ER)、黃體素受體 (Progesterone receptor)、第二型人類上皮生長因子受體 (Human epidermal growth factor receptor 2, HER2) 可將乳癌分為多個種類。目前治療乳癌的方式有局部性的外科手術、放射線治療,又或者是系統性的荷爾蒙治療、化療、標靶治療等,不論患者屬於何種乳癌,在治療時都須面對治療的副作用和高額的花費。因此,尋找毒性低、有效且成本低廉的抗乳癌藥物是當務之急。野馬追內酯A (Eupalinolide A) 屬倍半萜類化合物,目前已知具有抗肝癌的作用,然而對於乳癌的功效及機制目前仍是未知。本研究旨在探討eupalinolide A於小鼠三陰性乳癌細胞株JC上的抗腫瘤功效及機轉。從結果中發現,eupalinolide A造成JC細胞停滯於G2/M期。同時,eupalinolide A也會使得JC細胞產生細胞凋亡,透過增加細胞死亡配體FASL、TRAIL及死亡配體FAS,引發Caspase 8介導的外源路徑發生;此藥物也能改變粒線體膜電位,誘發Caspase 9主導的細胞凋亡內源路徑發生。再者,eupalinolide A能夠促使JC細胞大量發生細胞自噬。最後,利用NGS (Next Generation Sequencing) 結果,推測eupalinolide A透過誘使JC細胞內的氧化壓力累積,使得MAPK路徑活化,進而產生細胞週期停滯、細胞凋亡、細胞自噬等生物現象。綜上所述,eupalinolide A在抗三陰性乳癌的功效及治療上具有極大的潛力。
Breast cancer has become the most commonly diagnosed cancer in the world and ranks fifth among the leading causes of cancer-related deaths. Based on the surface receptors of breast cancer cells, namely estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2), breast cancer can be classified into various subtypes. Current treatment modalities for breast cancer include localized surgical procedures, radiation therapy, as well as systemic treatments such as hormone therapy, chemotherapy, targeted therapy, and others. Regardless of the subtype, patients undergoing breast cancer treatment often face side effects and high costs. Therefore, it is crucial to search for anti-breast cancer drugs that are low in toxicity, effective, and affordable. Eupalinolide A, a sesquiterpene compound, has been shown to possess anti-liver cancer properties, but its efficacy and mechanisms of action in breast cancer remain unknown. This study aims to investigate the anti-tumor effects and mechanisms of eupalinolide A in the mouse triple-negative breast cancer cell line JC. The results revealed that eupalinolide A induced cell cycle arrest at the G2/M phase in JC cells. Additionally, eupalinolide A induced apoptosis in JC cells through increased expression of the cell death ligands FASL, TRAIL, and death receptor FAS, leading to Caspase 8-mediated extrinsic pathway activation. The compound also altered mitochondrial membrane potential, inducing Caspase 9-mediated intrinsic pathway activation and cellular apoptosis. Furthermore, eupalinolide A promoted extensive autophagy in JC cells. Based on cellular experiments and next-generation sequencing results, it is speculated that eupalinolide A may accumulates oxidative stress within JC cells, leading to activation of the MAPK pathway and subsequent cell cycle arrest, apoptosis, and autophagy. In summary, eupalinolide A demonstrates great potential in the treatment of triple-negative breast cancer with significant anti-tumor effects.
摘要 i
Abstract ii
目次 iii
圖目次 v
第一章 緒論 1
1.乳癌 (Breast cancer) 1
1.1 乳癌發展現況 1
1.2 乳癌的分類 1
1.3 乳癌分期 3
1.4 乳癌治療策略 3
2.天然物 (Natural compounds) 4
2.1 天然物 4
2.2 野馬追內酯 A (Eupalinolide A) 4
3. 活性氧化物 (Reactive oxygen species, ROS) 5
4.程序性細胞死亡 (Programmed cell death) 5
4.1 細胞凋亡 (Apoptosis) 5
4.2 細胞自噬 (Autophagy) 7
5.細胞週期停滯 (Cell cycle arrest) 7
6.研究動機 8
第二章 材料與方法 9
1. 藥品配製 (Drug preparation) 9
2. 細胞繼代及培養 (Cell culture) 9
3. 細胞生存力試驗 (Cell viability assay) 9
4. 細胞週期分析 (Cell cycle analysis)10
5. 細胞凋亡檢測 (Annexin V assay) 10
6. 細胞凋亡蛋白酶活性測試 (Caspase activity assay) 11
7. 粒線體膜電位分析 (Mitochondria membrane potential assay) 11
8. 死亡配體、受體偵測 (Death ligand/receptor assay) 12
9. 西方墨點法 (Western-Blot) 12
9.1 蛋白質萃取與定量 (Protein extraction and BCA protein assay) 12
9.2聚丙烯酰胺凝膠電泳 (SDS-PAGE)13
10. 即時定量聚合酶連鎖反應 (Real-time quantitative PCR, RT-qPCR) 及次世 代定序 (RNA-sequencing) 13
11. 活性氧化物偵測 (Reactive oxygen species assay) 14
12. 細胞自噬偵測 (Acridine orange staining) 15
13. 統計分析 15
第三章 實驗結果 16
1. 不同濃度 eupalinolide A 處理對小鼠乳癌細胞及正常乳腺細胞生存之影響 16
2. Eupalinolide A 透過細胞週期抑制蛋白 p21 造成 JC 細胞停滯於 G2/M 期16
3. Eupalinolide A 誘導 JC 細胞產生細胞凋亡 17
4. 細胞凋亡內、外源路徑受到 Eupalinolide A 刺激而上升 17
5. Eupalinolide A 促使 JC 細胞發生細胞自噬 18
6. Eupalinolide A 造成 JC 細胞產生氧化壓力進而誘發細胞凋亡及細胞自噬的
發生 18
7. Eupalinolide A 造成 JC 細胞產生氧化壓力進而誘發細胞凋亡及細胞自噬的發生 19
第四章 討論 20
參考文獻 23
附註 50
附錄 51
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