博碩士論文 103881002 詳細資訊



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姓名 趙冠豪(GUAN-HAO ZHAO)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 研究哇巴因誘導的纖維細胞生長因子2釋放之分子機制
(Study on the molecular mechanisms of ouabain-induced FGF2 release)
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摘要(中) 強心苷哇巴因是一種具有毒性的天然化合物，但在醫學上以低劑量可以用於治療心力衰竭。它的主要生物作用是通過與鈉鉀泵阿爾法亞基結合後直接抑制鈉鉀泵的酶促活性及誘發伴隨的哇巴因相關的信號傳導。我們實驗室先前利用纖維細胞生長因子受體1(FGFR1)抑製劑SU5402和哇巴因處理A549細胞後，發現哇巴因通過FGF2/FGFR1信號傳導促使A549細胞分泌FGF2和活化FGFR1。為了深入闡明強心苷調節FGF2釋放的分子機制，我們首先依據可能之相關訊息傳遞，篩選了幾種訊息傳遞分子之抑制劑對哇巴因誘導的纖維細胞生長因子2釋放之影響，並使用HSA模型和Chou-Talalay來分析對A549細胞代謝活性有互相拮抗作用的信號傳導路徑。利用這些方法後發現ERK1/2抑製劑U0126強烈拮抗哇巴因誘導的細胞生長抑制，並且隨後的ELISA和Western blot分析顯示U0126減少了哇巴因促使的FGF2釋放和FGFR1磷酸化。另外，接著使用EGFR抑製劑吉非替尼和MKP1抑製劑NSC95397進一步證明了EGFR激活和MKP1減少各自部分地促使ERK1/2磷酸化。總而言之，強心苷哇巴因通過上游的EGFR磷酸化和MKP1減少來激活ERK1/2，從而促進FGF2釋放、FGF2/FGFR1信號傳導。
摘要(英) Cardiac glycoside ouabain is a nature occurring toxic compound but used medically in small doses to treat heart failure. Its primary biological action is to directly inhibit Na+/K+-ATPase enzymatic activity with concomitant ouabain-related signaling induction through binding to Na+/K+-ATPase α subunit. Our laboratory had previously utilized FGFR1 inhibitor SU5402 and ouabain to treat A549 cells and found ouabain promoted FGF2 secretion and FGFR1 activation in A549 cells via FGF2/FGFR1 signaling. To further elucidate the molecular mechanisms underlying cardiac glycoside-mediated FGF2 release, we first screened several compounds to identify small molecular inhibitors of signaling effectors that were able to antagonize to the ouabain effect in A549 cells using HSA model and Chou-Talalay method. These approaches discovered ERK1/2 inhibitor U0126 potently antagonized ouabain-mediated growth inhibition, and subsequent ELISA and Western blot analysis revealed U0126 reduced FGF2 release and FGFR1 phosphorylation mediated by ouabain. Both EGFR activation and MKP1 reduction were found to contribute to ERK1/2 phosphorylation as evidenced by pharmacological approaches using EGFR inhibitor Gefitinib and MKP1 inhibitor NSC95397. Therefore, we concluded that cardiac glycoside ouabain activated ERK1/2 via both upstream EGFR phosphorylation and MKP1 diminishment to promote FGF2 release and susequent FGF2/FGFR1 signaling in A549 cells.
關鍵字(中) ★ Ouabain
★ FGF2
★ ERK1/2
★ MKP1
★ EGFR
★ Na+/K+-ATPase α1		 關鍵字(英)
論文目次 摘要 i

ABSTRACT ii

Acknowledgements iii

Table of contents iv

Abbreviations vii

1. Introduction 1
Objectives: 8

2. Materials and methods 10
2-1. Chemicals and reagents 10
2-2. Cell culture 10
2-3. Cell viability assays 11
2-3-1. MTS assay 11
2-3-2. Trypan blue staining 12
2-4. Combined drug analysis 12
2-5. Enzyme-linked immunosorbent assay (ELISA) 13
2-6. Western blot analysis 13
2-7. Gene silencing 14
2-8. Stastical analysis 14

3. Results 16
3-1. Identification of inhibitors antagonizing ouabain-induced cellular effects. 16
3-2. U0126 suppressed ouabain-mediated FGF2 release and membrane integrity loss. 16
3-3. Suppression of MKP1 by ouabain and NSC95397 activated MAPKs and FGFR1. 18
3-4. The EGFR inhibitor Gefitinib retarded ouabain-activated ERK1/2 and FGFR1. 20
3-5. Knockdown of ATP1A1 had no effects on ERK1/2 and EGFR phosphorylation. 21

4. Discussions 23

5. Figures 33
Figure 1. Chemical structure of cardiac glycosides. 33
Figure 2. Structure and mechanism of pumping of the Na+/K+-ATPase. 34
Figure 3. Schematic diagram of FGF2 gene, mRNA transcript and protein isoforms. 35
Figure 4. The basic structure and splice variants of FGFRs. 36
Figure 5. Proposed model of unconventional secretion of FGF2. 37
Figure 6. Ouabain increased A549 cell membrane permeability. 38
Figure 7. U0126 antagonized ouabain-induced FGF2 release and plasma membrane compromise. 39
Figure 8. Repression of MKP1 activity by cardenolides or NSC95397 provoked MAPKs and FGFR1 activation. 41
Figure 9. Inhibition of EGFR phosphorylation by Gefitinib reduced ouabain-induced FGFR1 and ERK1/2 activation. 44
Figure 10. Knockdown of ATP1A1 did not affect ouabain-mediated EGFR and ERK1/2 phosphorylation. 46
Figure 11. Proposed mechanism of action of ouabain-induced cell signaling. 48

6. Tables 49
Table 1. Description of CI values for drug combinations and A549 cell viability using HSA model. 49
Table 2. Description of Fa and CI values for non-fixed ratio of drug combinations using Chou-Talalay method. 50

7. References 51

8. Appendices 66
Appendix 1. The cardenolides ouabain and reevesioside A regulate FGF2/FGFR1 in a dose- and time-dependent manner. 66
Appendix 2. Neither transcription nor proteolysis contributed to the decrease in intracellular protein levels of FGF2 upon treatment of cardenolides. 68
Appendix 3. SU5402, an inhibitor of FGFR1, antagonized FGFR1 activation and cell growth inhibition by cardenolides. 70
Appendix 4. Cardenolides activated ERK1/2 to promote FGF2 export in A549 cells. 72
Appendix 5. The EGFR inhibitor gefitinib decreased ouabain-induced activation of EGFR and downstream activation of ERK 1/2 but not JNK 1/2. 74
Appendix 6. MKP1 inhibition by NSC95397 resembled ouabain-induced activation of ERK1/2 and FGF2/FGFR1. 76
Appendix 7. Identification of inhibitors antagonizing ouabain-induced cell growth inhibition. 78
Appendix 8. Inhibition of ouabain-induced FGFR1 and ERK1/2 activation by LFM-A13 and U0126. 80
Appendix 9. Combined drug analyses using HSA model for discovering candidate inhibitors antagonized ouabain-induced cell growth inhibition. 81
Appendix 10. Growth inhibition curves of ouabain, LFM-A13, SU5402, LY294002 and U0126 against A549 cells. 83
Appendix 11. Fa-CI plots and bar charts of A549 cell viability for combined drug analyses using Chou-Talalay method. 84
Appendix 12. LFM-A13 and U0126 antagonized ouabain-induced FGFR1 and ERK1/2 activation. 86
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指導教授 李秀珠 審核日期 2020-9-23
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