臺灣博碩士論文加值系統

目前，在人類細胞中的環氧合酵素 (COX) 存在兩種獨特的異構物：cyclooxygenase-1 (COX-1) 和 cyclooxygenase-2 (COX-2)。COX-1 是一種能在組織中持續性表現之housekeeping 酵素而COX-2 是一種被誘導性酵素，細胞在受到發炎或細胞分裂刺激時會大量表現COX-2。已知由COX-1合成出的前列腺素會參與一般正常生理調控，然而由COX-2合成的前列腺素則主要參與許多過敏免疫性疾病及癌症的發生過程。
在細胞週期進行過程中，細胞週期會受到不同的週期素依賴性蛋白質激酶cyclin-dependent kinases (CDKs) 調控。已有很多研究指出癌細胞常有異常的細胞週期檢查點調控，因而造成不受控制的細胞生長；因此CDKs可作為除了COX-2之外另一個癌症治療的目標。在癌細胞中，COX-2已被證實具有穩定survivin (一種抗細胞凋亡蛋白) 的能力，而且survivin本身也會和CDK1及半胱胺酸蛋白酵素9 (caspase-9) 結合形成一個複合體，能夠調節細胞分裂期 (M phase) 的進行與細胞凋亡的抑制。因此，本篇研究探討在人類肺腫瘤細胞株A549中，NS-398 (一種選擇性的COX-2抑制劑) 對於抑制COX-2表現的訊息傳遞路徑。此外，我們也將探索NU6102 (一種選擇性的CDK1/2抑制劑) 是否也能夠對COX-2有抑制效果。
研究結果顯示，A549細胞在飢餓狀況刺激下會產生明顯COX-2的表現，且前列腺素E2受器 (EP2) 會參與NS-398所造成的COX-2抑制。有趣地， NU6102也會抑制A549內由飢餓引起的COX-2表現。當A549暴露在NS-398或NU6102時，細胞內三種有絲裂原活化蛋白激酶 (MAPK) 中只有胞外調節激酶 (ERK1/2) 明顯受到活化；且以PD098059 (一種MEK1抑制劑) 預先處理後，更加強COX-2被NS-398或NU6102抑制的效果。總結本研究結果，我們發現NS-398和NU6102都能夠抑制COX-2表現且A549細胞在受到外界刺激下會利用MEK/ERK訊息傳遞路徑來增加COX-2表現量。

At present, cyclooxygenase exists in two distinct isoforms: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in human cells. COX-1 is constitutively expressed as a housekeeping enzyme in tissues whereas COX-2 is an inducible enzyme that is rapidly induced by inflammatory and mitogenic stilmuli. It is known that prostaglandins (PGs) synthesized by COX-1 mediate normal physiological modulation while PGs synthesized by COX-2 are involved in many inflammatory diseases and cancer. During the progression of the cell cycle, the cell cycle is regulated by various cyclin-dependent kinases (CDKs). Many studies demonstrated that cancer cells often exhibit aberrant cell cycle regulation resulting in uncontrolled cell proliferation. Therefore, CDKs are another target for cancer therapies in addition to COX-2. It is worthy to notice that COX-2 was proved to stabilize survivin (an inhibitor of apoptosis) in cancer and survivin itself also associates with CDK1 and caspase-9 to form a complex that can modulate the progression of the mitotic phase and the inhibition of apoptosis. In our experiments, we investigated the signaling pathway involved in COX-2 inhibition by NS-398 in human lung carcinoma cell line A549. Moreover, we also examined whether NU6102 (a selective CDK1/2 inhibitor) has the potential to inhibit COX-2 expression. In this study, we found that COX-2 expression was significantly increased by starvation of A549 cells. Prostaglandins E2 receptor 2 (EP2) was found to be involved in COX-2 inhibition by NS-398. Interestingly, NU6102 was able to suppress starvation-induced COX-2 expression. Moreover, only ERK1/2 among three MAPKs was activated after A549 cells had been exposed to NS-398 or NU6102. PD098059, a specific inhibitor of MEK1, enhanced COX-2 inhibition by NS-398 or NU6102. In conclusion, we found that both NS-398 and NU6102 could inhibit COX-2 expression and the MEK/ERK signal pathway could be used to increase COX-2 expression in response to extracellular stimuli in A549 cells.

CHINESE ABSTRACT-----------------------------------------------------------I
ABSTRACT-------------------------------------------------------------------III
ACKNOWLEDGEMENTS-----------------------------------------------------------V
LIST OF FIGURES------------------------------------------------------------VIII
LIST OF APPENDIXES---------------------------------------------------------X
ABBREVIATIONS--------------------------------------------------------------XI
I. INTRODUCTION
1.1 The Arachidonic Acid Cascade-----------------------------------------1
1.2 Biosynthesis and Functions of Cyclooxygenase ------------------------1
1.3 Induction of Prostaglandins and PG Receptors-------------------------2
1.4 The Role of Cyclooxygenase in Cancer---------------------------------4
1.5 Usage of Selective COX-2 Inhibitors for Cancer Therapies-------------6
1.6 Introduction of CDKs and Relative Inhibitors in Cancer---------------7
1.7 Participation of CDK and COX-2 at the Mitotic Checkpoint-------------8
1.8 Various Responses of MAPKs to Extracellular Stimuli------------------9
Motive---------------------------------------------------------------------11
II. MATERIALS AND METHODS
2.1 Sources of Materials-------------------------------------------------12
2.2 Sources of Instruments-----------------------------------------------13
2.3 Solution Preparation for Cell Culture--------------------------------14
2.4 Thawing Cells and Subcultivation-------------------------------------14
2.5 Cryopreservation-----------------------------------------------------15
2.6 Counting Cells-------------------------------------------------------16
2.7 MTT Cell Viability Assay by 96-well Plate----------------------------16
2.8 Extraction of Total Protein------------------------------------------17
2.9 Bio-Rad Protein Assay------------------------------------------------18
2.10 SDS-PAGE and Protein Electrophoresis--------------------------------19
2.11 Western Blotting----------------------------------------------------21
III. RESULTS
3.1 Determination of the Concentration of NS-398 for Treatment
A549 Cells ----------------------------------------------------------22
3.2 Effect of Serum-Free Medium Treatment on COX-2 Expression------------22
3.3 Effect of NS-398 on Cyclooxygenase-2 Expression ---------------------22
3.4 Effect of NS-398 on Prostaglandin E2 Receptors Expression in
A549 Cells ----------------------------------------------------------23
3.5 Effect of Exogeneous PGE2 and PGE2 Analog on COX-2, EP1
and EP3 Expression --------------------------------------------------23
3.6 Effect of AH6809 on COX-2 and EP1, EP2 and EP3
Receptors Expression ------------------------------------------------24
3.7 Combination of NS-398 with AH6809 in Treating A549 Cells ------------25
3.8 Possible Correlations between CDKs and COX-2 in A549 Cells ----------25
3.9 Activation of MAPK Signaling Pathways by NS-398 and
NU6102 in A549 Cells ------------------------------------------------26
3.10 Involvement of the MEK/ERK Signaling Pathway in Regulation
of Inhibition of COX-2 Expression Caused by NS-398
and NU6102-------------------------------------------------------------26
IV. DISCUSSION-------------------------------------------------------------28
V. REFERENCES--------------------------------------------------------------33
VI. FIGURES----------------------------------------------------------------47
VII. APPENDIXES------------------------------------------------------------66

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