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系統識別號 U0026-0812200914012595
論文名稱(中文) 蟲草素對MA-10小鼠萊氏腫瘤細胞固醇類生成之機制探討
論文名稱(英文) THE MECHANISM OF CORDYCEPIN-INDUCED STEROIDOGENESIS IN MA-10 MOUSE LEYDIG TUMOR CELLS
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 95
學期 2
出版年 96
研究生(中文) 潘博雄
研究生(英文) Bo-Syong Pan
電子信箱 t9694103@mail.ncku.edu.tw
學號 t9694103
學位類別 碩士
語文別 英文
論文頁數 94頁
口試委員 指導教授-黃步敏
口試委員-楊西苑
口試委員-劉明毅
中文關鍵字 蟲草素  MA-10小鼠萊氏腫瘤細胞  固醇類生成 
英文關鍵字 CORDYCEPIN  STEROIDOGENESIS  MA-10 MOUSE LEYDIG TUMOR CELLS 
學科別分類
中文摘要 蟲草素(3'去氧腺嘌呤)最早是萃取自冬蟲夏草的菌絲體,它是一種腺嘌呤的類似物。我們先前的探討也證明,蟲草素可藉由與腺嘌呤受器結合,活化PKA-cAMP傳遞路徑進而調控固醇類速控蛋白的表現以刺激小鼠萊氏細胞睪固酮之生成。此外,我們也在小鼠的萊氏細胞與MA-10小鼠萊氏腫瘤細胞上偵測到A1,A2a,A2b及A3這四種腺嘌呤受器傳訊者核醣核酸的表現。以具有專一性的腺嘌呤拮抗劑與蟲草素一起處理萊氏細胞,我們發現A1,A2a及A3的拮抗劑能個別的抑制由蟲草素所刺激的睪固酮生成。然而,蟲草素是透過何種細胞機制去調控固醇類速控蛋白表現達成對小鼠萊氏細胞固醇類生成作用目前仍不清楚。在先前的研究中,MA-10小鼠萊氏腫瘤細胞廣泛的使用在固醇類生成細胞機制之探討。因此,本篇論文的目的在探討蟲草素對MA-10小鼠萊氏腫瘤細胞固醇類生成是藉由活化何種細胞機制進而調控固醇類速控蛋白表現。結果顯示,隨著時間與濃度的增加,蟲草素具有刺激MA-10小鼠萊氏腫瘤細胞黃體酮的生成。以具有專一性的腺嘌呤協同劑與蟲草素一起處理萊氏細胞,我們發現蟲草素對於A1,A2b及A3的腺嘌呤協同劑能個別的降低由腺嘌呤協同劑所刺激的黃體酮生成。西方點墨法的實驗結果顯示,蟲草素並不能有效的刺激固醇類速控蛋白在蛋白質上的表現。然而,當我們將含有固醇類速控蛋白促進子全長區域(-1.3k to +32)的載體送入MA-10小鼠萊氏腫瘤細胞內,蟲草素並不能有效的刺激固醇類速控蛋白促進子的表現。另一方面,當我們利用腺嘌呤接受器協同劑去分別刺激四種腺嘌呤接受器的表現時,發現A3腺嘌呤接受器協同劑和結抗劑可以大量的回復蟲草素帶來的死亡效果,也就是細胞的死亡被抑制了。因此,蟲草素可能藉由活化A3腺嘌呤接受器進而引發MA-10小鼠萊氏腫瘤細胞死亡。 總結,蟲草素可藉由與腺嘌呤受器結合,進而不藉由固醇類速控蛋白活化路徑來刺激MA-10小鼠萊氏腫瘤細胞黃體酮之生成。此外,蟲草素同時可能藉由活化A3腺嘌呤接受器進而引發MA-10小鼠萊氏腫瘤細胞死亡。
英文摘要 Cordycepin (3’ deoxyadenosine), the analogue of adenosine, is a pure component extracted from the mycelia of Cordyceps sinensis. It has been suggested that cordycepin can improve lung function and increase energy levels and sex drive. Our laboratory did observe that cordycepin acted through cAMP-dependent PKA signaling pathway to stimulate testosterone production, Steroidogenic acute regulatory protein (StAR) mRNA and StAR protein expressions in normal mouse Leydig cells. We have also demonstrated that the expression of different adenosine receptor subtypes, A1, A2a, A2b and A3 mRNA were detected in normal mouse Leydig cells and MA-10 mouse Leydig tumor cells. Besides, cordycepin-stimulated testosterone production could be suppressed by A1, A2b and A3 adenosine receptor antagonists in normal mouse Leydig cells, respectively. However, the mechanism in cordycepin-stimulated steroidogenesis remains unclear. In the present study, MA-10 mouse Leydig tumor cell line was used to investigate the cellular mechanism. The results showed that cordycepin could stimulate progesterone production with dose-dependent manner in MA-10 cells. By using selective adenosine receptor agonists to co-treat with cordycepin, the results demonstrate that cordycepin might act through adenosine receptor subtypes, A1, A2b and A3, but not A2a, to stimulate steroidogenesis in MA-10 mouse Leydig cells. Using immunoblotting assays, cordycepin could not induced the expression of StAR protein. Furthermore, MA-10 cells were transiently transfected with plasmid containing luciferase gene with 5’-flanking StAR promoter constructs between -1.3k to +32 region. However, 5’-deletion promoter analysis indicated that cordycepin did not increase StAR promoter activity. Taken together, cordycepin might act through adenosine receptor to induce the StAR-independent signal transduction pathway, and thus stimulate the progesterone production in MA-10 mouse Leydig tumor cells. Concurrently, in morphology and methylthiazolecterazolium (MTT) assays, selective A3 adenosine receptor agonist and antagonist could significantly rescue cordycepin-induced cell death in MA-10 mouse Leydig tumor cells. These evidences demonstrate the possible relationship between A3-AR and cordycepin-induced death-effect. In conclusion, cordycepin would stimulate MA-10 cell steroidogenesis through adenosine receptor to activate StAR-independent pathway. Furthermore, cordycepin could activate A3-AR to induce MA-10 cell death.
論文目次 Abstract in Chinese---------------------------------------------------------------I
Abstract----------------------------------------------------------------------------III
Acknowledgements --------------------------------------------------------------V
Table of Contents-----------------------------------------------------------------VI
List of Figures---------------------------------------------------------------------IX
Introduction------------------------------------------------------------------------1
Materials and Methods-----------------------------------------------------------8
Chemicals-----------------------------------------------------------------------8
Cell culture----------------------------------------------------------------------9
Radioimmunoassay (RIA) ---------------------------------------------------10
Transient transfection and luciferase assays-------------------------------10
Immunobloting analysis------------------------------------------------------11
MTT cytotoxicity assay-------------------------------------------------------12
Statistical analysis-------------------------------------------------------------12
Results------------------------------------------------------------------------------14
Cordycepin-induced steroidogenesis with dose-dependent manner in MA-10 mouse Leydig tumor cells---------------------------------------14
Cordycepin-induced steroidogenesis with time-dependent manner in MA-10 mouse Leydig tumor cells---------------------------------------14
Effects of cordycepin on adenosine receptor agonist induced steroidogenesis in MA-10 mouse Leydig tumor cells-----------------14
Effects of adenosine receptor antagonists on cordycepin-induced steroidogenesis in MA-10 mouse Leydig tumor cells----------------16
Cordycepin could not induce StAR protein expression in MA-10 cells---------------------------------------------------------------------------17
Cordycepin could not induce StAR promoter expression in MA-10 mouse Leydig tumor cells-------------------------------------------------17
The effect of adenosine receptor agonists on morphological change in MA-10 cells-----------------------------------------------------------------18
The death effect of adenosine receptor agonists on MA-10 cells--------------------------------------------------------------------------18
The effect of adenosine receptor agonists on morphological change in cordycepin-treated MA-10 cells-----------------------------------------19
The effects of adenosine receptor agonists on cordycepin-induced MA-10 cell death----------------------------------------------------------20
The effect of adenosine receptor antagonists on morphological change in MA-10 cells-------------------------------------------------------------21
The death effect of adenosine receptor antagonists on MA-10 cells--------------------------------------------------------------------------22
The effect of adenosine receptor antagonists on morphological change in cordycepin-treated MA-10 cells--------------------------------------23
The effects of adenosine receptor subtype antagonists on cordycepin-induced in MA-10 cell death-------------------------------23
Discussion-------------------------------------------------------------------------25
References-------------------------------------------------------------------------77
About the author------------------------------------------------------------------94
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