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研究生:黃士漢
研究生(外文):Shih-Han Huang
論文名稱:Rooibos Suppresses the Proliferation, Migration and Invasion of Human Prostate Cancer Cells
論文名稱(外文):南非國寶茶抑制人類前列腺癌細胞的增生遷移與侵入
指導教授:褚志斌褚志斌引用關係高永旭
指導教授(外文):Chih-Pin ChuuYung-Hsi Kao
學位類別:博士
校院名稱:國立中央大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文出版年:2020
畢業學年度:108
語文別:英文
論文頁數:122
中文關鍵詞:南非國寶茶前列腺癌凋亡增生遷移侵入
外文關鍵詞:RooibosProstate cancerApoptosisProliferationMigrationInvasion
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前列腺癌是常見的惡性腫瘤,在西方的國家中是排名第二的癌症死因。針對轉移型的前列腺癌,雄性素剝奪療法(ADT)是標準的治療方式。雖然去除雄性賀爾蒙能有效地使腫瘤消退,但大多數接受ADT治療的前列腺癌患者,腫瘤會在1-3年左右發展成賀爾蒙抗性前列腺癌(CRPC),至今對於CRPC仍然沒有一個很好的治療法,或推遲轉移性前列腺癌進程的方式。南非國寶茶Rooibos (Aspalathus linearis)是一種豆科類的灌木植物,在當地作為草本茶使用。南非國寶茶園生在南非西開普省的席德堡山脈,被認為是一種健康的茶飲,因為它無咖啡因且單寧含量低,曾經被報導指出具有抗氧化的活性。我們用了具有抗癌活性的GRT-綠色南非國寶茶(GRTTM; 12.78g aspalathin/ 100 g extract,以下簡稱GRT)萃取物進行CRPC的加藥試驗。在第一部分我們用LNCaP 104-R1細胞進行本次實驗研究,它是一株富含雄性素受體AR且為非賀爾蒙依賴的前列腺癌細胞,藉此用來模擬臨床上的CRPC。我們將LNCaP 104-R1細胞種於96孔盤之中,並且以不同濃度的GRT (10-100µg/ml)進行加藥處理,透過MTT以及Hoechst 33258染色生長測試的分析測定,證明GRT能夠抑制LNCaP 104-R1細胞的增生。透過流式細胞儀分析指出,經由GRT處理後的細胞,會增加G1以及G2/M期的細胞數,減少S時期的細胞數。彗星實驗也揭露了GRT會誘導前列腺癌細胞的DNA損傷。我們在去勢小鼠的皮下打入LNCaP 104-R1細胞,並透過管餵方式給予GRT (400mg/kg),能夠顯著地抑制腫瘤的生長。從Micro-Western Array中得知,經加藥處理GRT的LNCaP 104-R1細胞,調控生存與增生的蛋白表現量會下降,如AKT1, AKT2, AKT3, PKM2和MCL1,增加cytochrome C蛋白的表現。在細胞中過表達AKT,能夠減少GRT對於LNCaP 104-R1細胞增生的抑制,這也說明GRT的目標是AKT的訊息傳遞路徑。第二部分探討的是轉移,我們選用了C4-2B細胞,這是一株源於LNCaP的細胞,具有高度轉移到骨頭的特性。藉由transwell 實驗得知GRT能抑制LNCaP C4-2B細胞遷移與侵入。GRT處理細胞後會減少YAP, MST1, 磷酸化MST1-T183/ 磷酸化MST2-T180和paxillin,並增加E-cadherin蛋白量表現。在CRPC細胞中過表達YAP並加藥處理GRT,被抑制的遷移與侵入的現象能有部分被恢復。C4-2B細胞中加入GRT主要的類黃酮aspalathin會抑制細胞的遷移,過表達YAP會回復癌細胞的部分遷移能力。這些結果指出GRT以及其主要類黃酮aspalathin對於前列腺癌腫瘤生長與轉移有抑制效果,未來有開發為攝護腺癌輔助療法的潛力。
Prostate cancer (PCa) is one of the most common malignancy cancers in aged men. Androgen-deprivation therapy (ADT) is the standard treatment for advanced PCa. However, the majority of PCa patients receiving ADT will develop castration-resistant prostate cancer (CRPC) within 1-3years. Currently, there is no effective treatment for recurrent CRPC or PCa metastasis. Rooibos (Aspalathus linearis) is a shrub-like leguminous bush native to the Cedarberg Mountain in the Western Cape region of South Africa and is consumed as herbal tea. It is considered as healthy drink worldwide as it is caffeine-free and low in tannins, and it has been reported to exhibit antioxidant activity. We investigated the anti-cancer activity of aspalathin-rich green rooibos extract (GRTTM; 12.78g aspalathin/ 100 g extract) against CRPC cells. We used LNCaP 104-R1, a human AR-rich androgen-independent PCa cells, to mimic the clinical situation of CRPC. We demonstrated that GRT treatment (10-100µg/ml) suppressed the proliferation of LNCaP 104-R1 cells, as determined by MTT assay and Hoechst dye-based 96-well proliferation assay. Flow cytometry analysis indicated that GRT treatment increases the cell population in sub-G1 and G2/M phase but decreases the cell population in S phase. Comet assay revealed that GRT treatment induced DNA damage in PCa cells. Gavage of GRT (400mg/kg) reduced tumor growth of LNCaP 104-R1 xenograft in nude mice experiments. Micro-Western Array suggested that treatment with GRT (10-100µg/ml) decreased expression of proteins regulating cell proliferation and cell survival, including AKT1, AKT2, AKT3, PKM2, and MCL1, but increased protein expression cytochrome C. Over-expression of AKT rescued the suppressive effect of GRT, indicating that AKT signaling is the target of GRT. For metastasis study, we used LNCaP C4-2B cells, which were derived from bone metastasis of LNCaP sub-clone with high-metastatic activity. GRT treatment suppressed the cell migration and invasion as determined by transwell assay. GRT treatment decreased the protein expression of YAP, MST1, phospho-MST1-T183/ phospho-MST2-T180 and paxillin proteins but increased the level of E-cadherin. Over-expression of YAP rescued the suppressive effects of GRT on migration and invasion of CRPC cells. Treatment with the major flavonoid of GRT, the C-linked dihydrochalcone glucoside aspalathin (75-100 μg/ml), also reduced the migration of CRPC cells and the inhibition was partially rescued by YAP over-expression. These results suggested that GRT is a potential therapeutic agent for advanced PCa.
謝誌 I
ABSTRACT III
CONTENTS V
1. ABBREVIATIONS: 1
2. INTRODUCTION 4
2.1. PROSTATE AND PROSTATE CANCER 4
2.2. PROSTATE CANCER THERAPIES 5
2.3. ASPALATHUS LINEARIS /ROOIBOS 7
2.4. HIPPO-PATHWAY 8
2.5. APOPTOSIS 9
2.6. CELL CYCLE 10
2.7. AUTOPHAGY 11
2.8. ANTI-DIABETES AND ANTI-OBESITY EFFECTS OF ROOIBOS 12
3. MATERIALS AND METHODS 15
3.1. ROOIBOS EXTRACT GRT 15
3.2. CELL CULTURE 15
3.3. CELL PROLIFERATION ASSAY AND CHEMICALS 17
3.4. CELL VIABILITY ASSAY 17
3.5. IMMUNOFLUORESCENCE STAINING 18
3.6. FLOW CYTOMETRY ANALYSIS 19
3.7. WESTERN BLOT ANALYSIS 19
3.8. COMET ASSAY 20
3.9. XENOGRAFT EXPERIMENT IN NUDE MICE 21
3.10. OVEREXPRESSION TARGET PROTEIN 22
3.11. TRANSWELL ASSAY 22
3.12. MICRO-WESTERN ARRAY 23
3.13. STATISTICAL ANALYSIS 24
4. RESULT 25
PART 1: ROOIBOS SUPPRESSES PROLIFERATION OF CASTRATION-RESISTANT PROSTATE CANCER CELLS VIA INHIBITION OF AKT SIGNALING 25
4.1. GRT SUPPRESSED PROLIFERATION OF CASTRATION-RESISTANT PROSTATE CANCER CELLS 25
4.2. GRT TREATMENT CAUSED CELL CYCLE ARREST AND INDUCED APOPTOSIS IN CRPC CELLS 26
4.3. GRT GAVAGE SUPPRESSED TUMOR GROWTH OF LNCAP 104-R1 XENOGRAFTS IN NUDE MICE 27
4.4. GRT TREATMENT AFFECTED SIGNALING PROTEINS IN LNCAP 104-R1 CELLS 27
4.5. OVEREXPRESSION OF AKT1 RESCUED GRT-INDUCED GROWTH INHIBITION IN CRPC CELLS 28
PART 2: ASPALATHIN-RICH GREEN ASPALATHUS LINEARIS EXTRACT SUPPRESSES MIGRATION AND INVASION OF HUMAN CASTRATION-RESISTANT PROSTATE CANCER CELLS VIA INHIBITION OF YAP SIGNALING 30
4.6. EFFECT OF GRT TREATMENT ON THE MIGRATION AND INVASION OF PROSTATE CANCER CELLS 30
4.7. MICRO-WESTERN ARRAY AND WESTERN BLOTTING REVEALED THAT GRT TREATMENT SUPPRESSED EXPRESSION OF PROTEINS IN THE HIPPO-YAP SIGNALING PATHWAY 31
4.8. OVER-EXPRESSION OF YAP RESCUED THE SUPPRESSIVE EFFECTS OF GRT ON MIGRATION AND INVASION OF PROSTATE CANCER CELLS 31
4.9. ASPALATHIN TREATMENT SUPPRESSED THE MIGRATION OF PCA CELLS VIA INHIBITION OF YAP 32
4.10. GRT TREATMENT SUPPRESSED MIGRATION AND PROTEIN EXPRESSION OF YAP IN 22RV1 PCA CELLS 32
4.11. INHIBITORY OF GRT ON MIGRATION OF PROSTATE CANCER CELLS AS COMPARED TO OTHER NATURAL COMPOUNDS AND CHEMOTHERAPY DRUGS. 32
PART 3: ROOIBOS (ASPALATHUS LINEARIS) EXTRACT SUPPRESSES BODY WEIGHT AND DECREASE LIPID ACCUMULATION IN DB/DB MICE. 34
4.12. GRT GAVAGE DECREASE THE BODY WEIGHT OF DB/DB MICE 34
4.13. GRT DECREASE THE FAT ACCUMULATION IN FAT TISSUE 34
PART 4: GRT INDUCED APOPTOSIS IN ENZALUTAMIDE MDV3100 HUMAN PROSTATE CANCER CELLS. 35
4.14. EFFECT OF ENZALUTAMIDE MDV3100 ON PARENTAL C4-2 AND ENZALUTAMIDE MDV3100 RESISTANT C4-2 CELLS VIABILITY. 35
4.15. GRT SUPPRESS PROLIFERATION AND INDUCE APOPTOSIS IN MDV3100R. 35
4.16. THE PROTEIN EXPRESSION OF C4-2 MDV3100R 36
4.17. GRT DECREASE THE MDV3100R COLONY FORMATION 36
5. DISCUSSION AND FUTURE DIRECTION 37
6. FIGURES AND FIGURE LEGENDS 44
6.1. FIGURE 1. 44
6.2. FIGURE 2. 45
6.3. FIGURE 3. 46
6.4. FIGURE 4. 48
6.5. FIGURE 5. 50
6.6. FIGURE 6. 51
6.7. FIGURE 7. 53
6.8. FIGURE 8. 54
6.9. FIGURE 9. 55
6.10. FIGURE 10. 56
6.11. FIGURE 11. 58
6.12. FIGURE 12. 60
6.13. FIGURE 13. 61
6.14. FIGURE 14. 62
6.15. FIGURE 15. 63
6.16. FIGURE 16 64
6.17. FIGURE 17. 65
6.18. FIGURE 18 66
6.19. FIGURE 19. 68
6.20. FIGURE 20. 69
6.21. FIGURE 21 71
6.22. FIGURE 22. 72
6.23. FIGURE 23. 73
6.24. FIGURE 24. 74
6.25 FIGURE 25. 75
6.26 FIGURE 26. 76
6.27 FIGURE 27. 77
6.28 FIGURE 28. 78
6.29 FIGURE 29. 79
6.30 FIGURE 30. 80
6.31 FIGURE 31. 81
6.32 FIGURE 32. 82
7. REFERENCES 83
8. TABLE 93
8.1. TABLE 1. 93
8.2. TABLE 2. 96
8.3. TABLE 3. 99
9. APPENDIX 101
9.1. PROSTATE CANCER METASTATIC CASCADE. 101
9.2. HIGH-THROUGHPUT MICRO-WESTERN ARRAYS PROFILE. 102
9.3. HIPPO PATHWAY'S SIGNAL TRANSMISSION CASCADE AND ITS FUNCTION REGULATION 103
9.4. APOPTOSIS SIGNALING TRANSDUCTION 104
9.5. CELL CYCLE 105
9.6. PROCESS OF AUTOPHAGY 106
9.7. ROOIBOS ENRICH COMPOUNDS 107
9.8. ORAL GRT MICE WEIGHT RECORD 108
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