Kotomolide A 誘導非小細胞癌細胞株A549細胞週期停滯與細胞凋亡之探討

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Title:	Kotomolide A 誘導非小細胞癌細胞株A549細胞週期停滯與細胞凋亡之探討 Kotomolide A arrests cell cycle progression and induces apoptosis in human non-small cell lung cancer A549 cells
Authors:	蔡伃婕
Contributors:	田乃月郭柏麟嘉南藥理科技大學：生物科技系暨研究所
Keywords:	人類非小細胞肺癌 Kotomolide A 細胞凋亡細胞週期粒線體途徑 p53 ATM Human non-small cell lung cancer cells Kotomolide A Apoptosis Cell cycle Mitochondrial pathway
Date:	2010
Issue Date:	2010-10-12 15:12:01 (UTC+8)
Abstract:	本篇論文首次研究Kotomolide A(KTA)在人類非小細胞肺癌細胞株A549中的抗癌效果。研究結果顯示KTA確實可以有效抑制人類非小細胞肺癌細胞株A549增生，並造成細胞週期停滯與誘導細胞走向細胞凋亡的途徑。其中關於阻斷細胞週期進行的部分，則與ATM活性的增加具有密切關係的。KTA是透過活化ATM使p53在serine15位置磷酸化，使得p53與MDM2的結合能力下降，並增加p53的穩定性。再者，KTA透過降低cyclinB1、cyclinA、cdc2與cdc25c，以及增加Chk2、cdc25c與cdc2的磷酸化，使細胞週期停滯在G2/M期。使用ATM的抑制劑caffeine進行實驗後，發現確實可以抑制細胞週期停滯在G2/M期的情形，並抑制KTA所誘導的p53(serine15)和Chk2的磷酸化狀況。另外在細胞凋亡方面，KTA透過改變Bax/Bcl-2的比例，導致粒線體膜電位降低並活化caspase9，最後引發粒線體途徑的細胞凋亡。綜合以上實驗結果可證實，KTA誘導人類非小細胞肺癌細胞株A549的細胞週期停滯與細胞凋亡的過程中，ATM與p53扮演著極為重要的角色。 This study first investigates the anticancer effect of Kotomolide A (KTA) in human non-small cell lung cancer cells, A549. KTA has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased the activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by KTA phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, KTA-mediated G2/M phase arrest also was associated with the decrease in the amounts of cyclinB1, cyclinA, Cdc2 and Cdc25C and increase in the phosphorylation of Chk2, Cdc25C and Cdc2. Specific ATM inhibitor, caffeine, significantly decreased KTA-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. KTA treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss and caspase- 9 activation. Taken together, these results suggest a critical role for ATM and p53 in KTA-induced G2/M arrest and apoptosis of human non-small cell lung cancer cells.
Relation:	校內外完全公開，學年度：98，72頁
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Dissertations and Theses

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