Flavokawain A對人類黑色素細胞癌抗增生的機制

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Title:	Flavokawain A對人類黑色素細胞癌抗增生的機制 The antiproliferative mechanism of flavokawain A in human melanoma cells
Authors:	陳胤伊 Yin-yi Chen
Contributors:	郭柏麟嘉南藥理科技大學：生物科技研究所
Keywords:	細胞週期細胞凋亡黑色素細胞癌 Apoptosis Melanoma cell cycle ERK PKCδ JNK p38
Date:	2008
Issue Date:	2008-12-29 15:22:22 (UTC+8)
Abstract:	本研究利用flavokawain A為研究主題，分析其對人類黑色素細胞癌A375.S2和MeWO細胞的抗增生活性及其相關機轉。研究結果顯示，flavokawain A處理細胞後，明顯抑制兩株細胞的增生，且呈現濃度依賴效應。在細胞週期方面，flavokawain A造成A375.S2明顯減少cyclin A，cyclin B1，cyclin E和cdc2蛋白的表現，且增加cdc2和cdc25C磷酸化，因此使細胞停滯在G2/M期。但相對的，flavokawain A不會影響MeWO細胞在細胞週期的分布及其相關調節的分子。在flavokawain A處理A375.S2和MeWO細胞後，藉由粒線體膜電位下降，增加Bak和Bax蛋白表現且減少Bcl-2和Bcl-XL蛋白的表現，活化caspase-9，進而觸發粒線體路徑；再者，由於caspase-9的抑制劑可有效抑制flavokawain A所造成的細胞凋亡，因此推斷粒線體死亡路徑參與flavokawain A所造成的細胞凋亡。此外，實驗結果也發現，flavokawain A可同時活化ERK1/2、p38、JNK以及PKCδ。所以本研究推測，flavokawain A在人類黑色素細胞癌抗增生的活性主要透過：A375.S2細胞在細胞週期停滯以及觸發粒線體路徑、MAPK路徑和PKCδ路徑而誘導癌細胞凋亡；而MeWO細胞則透過了啟動粒線體路徑、MAPK路徑及PKCδ路徑誘發癌細胞凋亡。 In this study, we first report the chemopreventive effect of flavokawain A in two human melanoma cancer cell lines, A375.S2 and MeWO. Treatment with flavokawain A decreased the cell proliferation of A375.S2 and MeWO cells in a dose dependent manner. Flavokawain A treatment arrested A375.S2 cells at G2/M phase. This effect was strongly associated with concomitant decrease in the level of cyclin A, cyclin B1, cyclin E and cdc2, and increase inactive phosphorylation of cdc2 and cdc25C. In contrast, flavokawain A failed to affect the distribution of cell cycle and related regulation factor in MeWO. Flavokawain A triggered the mitochondrial apoptotic signaling by changing the expression of Bcl-2 family proteins, resulting in mitochondrial membrane potential loss and caspase-9 activation. In addition, caspase-9 inhibitor pretrement flavokawain A decreased flavokawain A-induced apoptosis, suggesting mitochondrial apoptotic pathway is involved in apoptosis induced by flavokawain A. Moreover, we also found that mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2), p38 and c-Jun N-terminal kinase (JNK) and PKCδ, all are activated by flavokawain A treatment in A375.S2 and MeWO cells. Taken together, our study suggests that the blockade of initiation of cell apoptotic system may participate in the antiproliferative activity of flavokawain A in human melanoma cancer cells.
Relation:	校內校外均不公開
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Dissertations and Theses

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