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系統識別號 U0026-0402201211305900
論文名稱(中文) 新穎涎酸轉移酶抑制劑於抑制FAK/paxillin和血管新生訊息傳遞以及癌轉移抑制之角色探討
論文名稱(英文) A novel sialyltransferase inhibitor suppresses FAK/paxillin and angiogenesis signaling and cancer metastasis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 1
出版年 101
研究生(中文) 陳家揚
研究生(英文) Jia-Yang Chen
電子信箱 b90606019@ntu.edu.tw
學號 s5896103
學位類別 博士
語文別 英文
論文頁數 94頁
口試委員 指導教授-王憶卿
口試委員-郭明良
口試委員-張俊彥
口試委員-呂增宏
口試委員-呂佩融
口試委員-鄭宏祺
中文關鍵字 癌症轉移  血管新生  涎酸轉移酶  石膽酸  FAK訊息傳遞 
英文關鍵字 cancer metastasis  angiogenesis  sialyltransferase  lithocholic acid  FAK signaling 
學科別分類
中文摘要 背景介紹: 癌症為全世界疾病死亡原因之首位,而造成癌症死亡的主要原因為癌症復發或轉移,但針對癌症轉移的抑制性藥物截至目前為止仍然少見;涎酸轉移酶的過度表達已被報導會增加癌細胞表面涎酸化修飾,進而增加癌細胞轉移能力,並與癌症病人較差的預後有相關性。為了抑制癌症的轉移,本研究發展了新穎的涎酸轉移酶抑制劑Lith-O-Asp,並探討其對於抑制癌細胞轉移、抑制癌細胞血管新生之能力與機制。
實驗結果: 本研究首先確認涎酸轉移酶的mRNA於高轉移潛力的肺癌細胞中具有較高的表現量,酵素活性檢測結果顯示,Lith-O-Asp處理後,可以顯著的抑制肺癌細胞涎酸轉移酶的活性,並且在電腦分子模擬對接中預測Lith-O-Asp可藉由競爭結合於涎酸轉移酶之雙醣結合位置,而達到抑制其活性之效果。此外在細胞模式實驗中發現,Lith-O-Asp之處理,對於不同癌細胞株不具有細胞毒殺性,且經Lith-O-Asp處理之不同癌細胞株,其細胞移動能力、侵犯能力、與血管新生能力皆受到顯著抑制;再者,Lith-O-Asp的處理,可顯著抑制因過量表達alpha-2,3或alpha-2,6涎酸轉移酶所增進的癌細胞侵犯能力。而在動物模式中,Lith-O-Asp的處理可顯著抑制小鼠體內癌細胞之轉移。在機制作用方面,本研究發現Lith-O-Asp是藉由減少細胞表面integrin-beta1之alpha-2,3-以及alpha-2,6-涎酸化修飾,而抑制FAK以及paxillin之磷酸化活化,進而抑制其下游細胞間質金屬蛋白酶MMP2及MMP9之表現,並且抑制actin filament動態調節蛋白Rho之活性。另外,為了找尋有別於涎酸轉移酶之其他可能受影響的目標蛋白,本研究以二維電泳與質譜儀分析,發現Lith-O-Asp處理會改變許多與癌細胞轉移或血管新生作用相關蛋白之表現量或磷酸化程度,例如vimentin與RNH1。
研究結論: 本研究結果證實涎酸轉移酶抑制劑Lith-O-Asp,可藉由抑制FAK/paxillin訊息傳遞路徑與血管新生因子進而抑制癌細胞之轉移,並提供充分的證據支持Lith-O-Asp具有藥物開發之試驗與應用價值。
英文摘要 Background: Cancer recurrence and metastasis is the most common reason of disease death worldwide, but there are only a few drugs that specifically inhibit metastasis of tumor cells. Increased sialyltransferase (ST) activity promotes cancer cell metastasis, and overexpression of cell surface sialic acid correlates with poor prognosis in cancer patients. To seek therapies targeting metastasis for cancer treatment, this study developed a novel ST inhibitor, Lith-O-Asp, and investigated its anti-metastatic and anti-angiogenic effects and mechanisms.
Results: The present study first confirmed that more metastatic cancer cells did express higher mRNAs of various STs. Cells treated with Lith-O-Asp showed a reduction of activity on various ST enzymes by in vitro and cell-based activity analyses. Molecular docking suggested that Lith-O-Asp bound at disaccharide binding site of ST to inhibit its activity. Lith-O-Asp inhibited migration and invasion abilities in various cancer cell lines without cytotoxic effect, and showed inhibitory effect on the angiogenic activity of HUVEC endothelial cells. Indeed, Lith-O-Asp treatment consequently delayed cancer cell metastasis in experimental and spontaneous metastasis assays in animal model. Importantly, Lith-O-Asp decreased the alpha-2,3- and alpha-2,6-sialylation modification of integrin-β1 and inhibited the expression of phospho-FAK, phospho-paxillin, and the matrix metalloproteases MMP2 and MMP9. Lith-O-Asp attenuated the Rho GTPase activity leading to actin dynamic impairment. In addition, 2DE-MS/MS and immunoblotting analyses showed that Lith-O-Asp altered the protein expression level and phosphorylation status of various proteins involved in crucial metastasis and angiogenesis pathways such as vimentin and ribonuclease/angiogenin inhibitor RNH1. Furthermore, Lith-O-Asp treatment significantly inhibited the invasive ability exerted by ectopic overexpression of various ST enzymes catalyzing alpha-2,6- or alpha-2,3-sialylation.
Conclusions: The results of the current study provided compelling evidence that the potential pan-ST inhibitor, Lith-O-Asp, suppressed cancer cell metastasis likely by inhibiting FAK/paxillin signaling and expressing anti-angiogenesis factors. Lith-O-Asp is worthy for further testing as a novel anti-metastasis drug for cancer treatment.
論文目次 中文摘要.................................................. I
Abstract................................................ II
誌謝..................................................... IV
CONTENTS............................................... VI
TABLE CONTENTS......................................... VIII
FIGURE CONTENTS.........................................IX
APPENDIX CONTENTS...................................... XI
ABBREVIATION........................................... XII
Ⅰ. Introduction........................................ 1
1. Outline in Cancer.............................. 1
2. Commonly used Therapeutic Compounds............ 1
3. Sialyltransferases............................. 3
4. Sialylated Antigens............................ 4
(4.1). Thomsen-Friedenreich-related antigens.......... 4
(4.2). Sialyl Lewis antigens.......................... 5
(4.3). Sialyl alpha-2,6-lactosaminyl antigen.......... 5
(4.4). Poly-2,8-sialylation........................... 6
(4.5). Gangliosides sialylation....................... 6
5. Sialyltransferase in Cancer.................... 7
6. Sialyltransferase Inhibitors................... 8
7. Novel Synthetic Sialyltransferase Inhibitor, Lith-O-Asp.................................................... 9
Ⅱ. Specific Aims........................................ 11
Ⅲ. Materials and Methods............................... 12
1. Cell line used and cell culture................ 12
2. Compounds used and in vitro activity assay..... 12
3. Molecular modeling docking..................... 13
4. MTT cytotoxicity analysis...................... 14
5. Reverse-transcriptase polymerase chain reaction (RT-PCR)................................................... 14
6. Ectopic expression and siRNA knockdown of sialyltransferase...................................... 15
7. Two-dimensional gen electrophoresis (2DE) and MALDI-TOF-MS/MS analysis..................................... 15
8. Western blot analysis.......................... 16
9. Immunoprecipitation (IP)-Western blot analysis. 17
10. Immunocytochemistry staining................... 17
11. Lectin affinity assay followed by IP-Western blotting............................................... 18
12. Flow cytometry analysis......................... 1813. Wound healing assay............................ 19
14. Trans-well invasion assay...................... 20
15. Tube-formation assay........................... 20
16. In vivo spontaneous metastasis assay........... 21
17. In vivo experimental metastasis assay.......... 21
18. Biochemistry and hematology tests.............. 22
Ⅳ. Results............................................. 23
1. Increased sialyltransferase expression correlated with enhanced metastatic potential................ 23
2. Lith-O-Asp inhibits both alpha-2,3- and alpha-2,6-sialyltransferase activities........................... 24
3. Molecular modeling of Lith-O-Asp binding to mammalian sialyltransferase............................. 24
4. Lith-O-Asp inhibits migration and invasion abilities of cancer cells........................................ 25
5. Lith-O-Asp exhibits in vivo spontaneous and experimental metastasis inhibition..................... 25
6. Lith-O-Asp participates in anti-angiogenesis progression............................................ 27
7. Lith-O-Asp decreases cell migration ability through inhibition of integrin sialylation and FAK/paxillin signaling pathway...................................... 27
8. Lith-O-Asp takes part in cancer metastasis suppression in multiple ways revealed by proteomic studies................................................. 28
9. Reduction of metastasis by Lith-O-Asp is mediated through inhibition of sialyltransferases.............. 29
Ⅴ. Discussion.......................................... 31
Ⅵ. References.......................................... 37
Ⅶ. Tables.............................................. 47
Ⅷ. Figures............................................ 49
Ⅸ. Appendix............................................ 72
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