臺灣博碩士論文加值系統

根據世界衛生組織的資料，在2020年乳癌是世界上最常見也是最容易造成死亡的女性癌症，在一些臨床研究發現，血液中過低的脂聯素濃度是許多癌症的危險因子，其中就包括乳癌。脂聯素是一個大約30kDa的蛋白質，主要是由脂肪細胞所表現及分泌，在血液中的濃度與身體的脂肪量成反比，先前的研究指出脂聯素具有毒殺乳癌及肝癌細胞的能力，然而，發展蛋白質藥物最大的困境就是難以避免蛋白質聚合，同時也要確保蛋白質的穩定度及效力，因此不易發展成臨床用藥。在2013年，Kadowaki團隊發現一種小分子脂聯素促效劑AdipoRon，AdipoRon能夠促進肝臟及骨骼肌細胞的脂肪酸氧化，利用飲食誘導肥胖的小鼠模型，進行口服餵藥，發現AdipoRon能夠降低血糖濃度以及胰島素抗性。其他研究發現AdipoRon能夠促進胰臟癌細胞、卵巢癌細胞以及骨肉瘤細胞死亡，並促使上述細胞的細胞週期停留在G0/G1期。此外，利用小鼠模型也發現AdipoRon能夠抑制三陰性乳癌以及胰臟癌腫瘤的生長，因此本篇研究想探討AdipoRon抑制乳癌細胞生長的機制。
我們發現AdipoRon會抑制乳癌細胞生長、抑制腫瘤球形成、促進細胞週期停留在G0/G1時期、細胞凋亡、細胞自噬作用以及鐵依賴型細胞死亡。另外合併AdipoRon以及鐵依賴型細胞死亡抑制劑Ferrostatin-1，發現合併藥物能夠降低AdipoRon毒殺細胞的效果，因此推測AdipoRon主要是藉由鐵依賴型細胞死亡造成癌細胞凋亡。此外，我們也發現AdipoRon會使細胞以及粒線體中過氧化物堆積、粒線體數量下降以及粒線體型態改變，導致粒線體功能異常。
綜合以上所述，本篇研究發現AdipoRon可能藉由鐵依賴型細胞死亡造成乳癌細胞死亡，同時也發現AdipoRon能夠抑制乳癌腫瘤球的形成，顯示AdipoRon可能具有抑制癌細胞幹性的作用，不過AdipoRon造成鐵依賴型細胞死亡以及抑制癌細胞幹性的詳細機制需要更進一步的研究。

According to the data from The World Health Organization, breast cancer is the most common cancer worldwide and the leading cause of cancer death in women in 2020. Clinical studies indicate that lower adiponectin concentration in blood correlates with higher risk of breast, gastric, colorectal, and prostate cancer. Adiponectin, a ~30kDa protein, is produced and secreted by adipocytes. The concentration of adiponectin in blood negatively correlates with the mass of fat. In previous studies, adiponectin induces cell death of breast cancer cells and hepatocellular carcinoma cells. However, prevention of protein aggregation, and maintenance of protein stability and activity are the main challenges of developing protein drugs. Thus, in 2013, an adiponectin receptor agonist, AdipoRon, was identified by Kadowaki’s team. It has been found that AdipoRon induces fatty acid consumption in muscle and liver cells. Also, orally administered AdipoRon reduces blood glucose and insulin resistance in diet-induced obesity mouse models. Besides, AdipoRon induces cell death and G0/G1 arrest in pancreatic cancer cells, ovarian cancer cells, and osteosarcoma cells. Furthermore, AdipoRon inhibits tumor growth of breast and pancreatic cancer in mouse models. Therefore, AdipoRon is considered a potential therapeutic agent for breast cancer. In this study, we aim to investigate the effects of AdipoRon on breast cancer cells and the underlying mechanisms.
We found that AdipoRon induced cell arrest in G0/G1 phase, apoptosis, autophagy, ferroptosis, and inhibited stemness in breast cancer cells. Furthermore, we found that ferroptosis inhibitor, Ferrostatin-1, reduced the cytotoxic effect of AdipoRon, suggesting that AdipoRon-induced cell death was mediated by ferroptosis. Additionally, we found that AdipoRon decreased mitochondrial mass, altered the mitochondrial morphology, and induced mitochondrial dysfunction.
Altogether, this study suggested that AdipoRon-induced cell death was mediated by ferroptosis. We also found that AdipoRon was able to inhibit tumorsphere formation. However, it still needs further investigation to clarify the underlying mechanisms of how AdipoRon induces ferroptosis and how AdipoRon inhibits cancer stemness.

致謝 I
中文摘要 II
Abstract IV
List of Abbreviations VI
List of Figure VIII
Table of Contents X
Chapter 1 Introduction 1
1.1 Breast cancer 1
1.2 Adiponectin 2
1.2.1 Introduction of Adiponectin 2
1.2.2 Physiological Functions of Adiponectin 3
1.2.3 Adiponectin and Diseases 4
1.2.4 Adiponectin and Cancers 5
1.3 AdipoRon 6
1.3.1 Introduction of AdipoRon 6
1.3.2 AdipoRon as a potential treatment for diseases 7
1.3.3 AdipoRon as a potential therapeutic strategy for cancers 7
1.4 Autophagy 8
1.5 Ferroptosis 9
1.5.1 Mechanism of ferroptosis 9
1.5.2 Targeting ferroptosis as a therapeutic strategy in cancers 12
1.6 Mitochondrial dysfunction 14
Chapter 2 Specific Aim 19
Chapter 3 Materials and Methods 20
3.1 Materials used in this study. 20
3.1.1 Cells used in this study. 20
3.1.2 Cell-culture medium used in this study. 21
3.1.3 List of shRNAs. 22
3.1.4 List of primers. 23
3.1.5 List of antibodies. 24
3.2 Methods. 25
3.2.1 Cell culture and reagents. 25
3.2.2 Virus production and transduction. 25
3.2.3 Clonogenic survival assay. 27
3.2.4 Tumorsphere formation assay. 28
3.2.5 Cell viability assay. 28
3.2.6 Cell cycle assay. 29
3.2.7 Apoptosis assay. 29
3.2.8 SDS-PAGE and Western blot. 30
3.2.9 RNA extraction, cDNA synthesis, and quantitative polymerase chain reaction (RT-qPCR) 30
3.2.10 mRFP-GFP-LC3 Tandem Fluorescent Protein Quenching Assay 31
3.2.11 ROS analysis. 32
3.2.12 Mitochondrial morphology analysis. 34
3.2.13 Seahorse Mitostress assay. 35
3.2.14 Statistical analysis. 36
Chapter 4 Results 37
4.1 AdipoRon inhibited cell growth and cancer stemness of breast cancer cells. 37
4.2 AdipoRon induced the G0/G1 phase arrest in breast cancer cells. 38
4.3 AdipoRon slightly induced apoptosis and necrosis in breast cancer cells. 39
4.4 AdipoRon induced autophagy in breast cancer cells. 39
4.5 AdipoRon-induced LC3 conversion was not altered after inhibition of classical autophagy pathway. 41
4.6 AdipoRon reduced GPX4 expression level and induced ferroptosis in breast cancer cells. 42
4.7 AdipoRon induced mitochondrial dysfunction and ROS accumulation in breast cancer cells. 43
Chapter 5 Discussion 46
Figures 52
References 72

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