Destruxin E, a cyclodepsipeptide antibiotic, reduces cyclin D1 levels and inhibits anchorage-independent growth of v-Ki-ras-expressed pMAM-ras-REF cells
Destruxin E, a cyclodepsipeptide antibiotic, reduces cyclin D1 levels and inhibits anchorage-independent growth of v-Ki-ras-expressed pMAM-ras-REF cells
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DOI：
10.1248/bpb.27.587
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发表时间：
2004-04-01
影响因子：
2
通讯作者：
Tsuchiya, K
中科院分区：
文献类型：
--
作者：
Kobayashi, T;Ikeno, S;Tsuchiya, K
从绿僵菌（Metarhizium sp.MA324）发酵液中分离得到的环缩酚酸肽（DE）能抑制表达v-Ki-ras的pMAM-ras-REF（rasREF）细胞的生长（锚定独立）文化（a）更强烈的比在基质附着（贴壁依赖性）培养物（B）或v-Ki-ras-未表达的pMAM-ras-REF（REF）细胞在基质附着培养物中的培养物（c）; DE的IC 50值为0.07 μ M（a）、0.4 μ M（B）和1.2 μ M（c）。DE阻滞了基质附着培养物中rasREF细胞的G1期细胞周期进程（B）。在悬浮培养中用DE处理72小时的rasREF细胞中（a），细胞周期蛋白D1、细胞周期蛋白A、p27（Kip 1）和过度磷酸化Rb的水平降低，但cdk 4、cdk 6、cdk 2、p16（INK 4a）和p21（Cip 1）的水平不受影响。在这些影响中，细胞周期蛋白D1的减少是突出的。DE在悬浮培养物（a）中以0.1 μ M和在基质附着培养物（B）中以1 μ M降低rasREF细胞中的细胞周期蛋白D1水平，而在基质附着培养物（c）中以1 μ M不降低细胞周期蛋白D1水平。生长抑制的程度与细胞周期蛋白D1的减少相关。悬浮培养物（a）中rasREF细胞的细胞周期蛋白D1 mRNA水平也被DE降低。DE降低细胞周期蛋白D1的mRNA，导致rasREF细胞的锚定非依赖性生长的抑制。
Destruxin E (DE), a cyclodepsipeptide isolated from fermentation broths of Metarhizium sp. MA324, inhibited the growth of v-Ki-ras-expressed pMAM-ras-REF (rasREF) cells in the suspension (anchorage-independent) culture (a) more strongly than that in the substratum-attached (anchorage-dependent) culture (b) or that of v-Ki-ras-unexpressed pMAM-ras-REF (REF) cells in the substratum-attached culture (c); the IC50 values of DE were 0.07 muM (a), 0.4 muM (b), and 1.2 muM (c). DE arrested G1 phase cell cycle progression of rasREF cells in the substratum-attached culture (b). In rasREF cells treated with DE for 72 h in suspension culture (a), the levels of cyclin D1, cyclin A, p27(Kip1), and hyperphosphorylated Rb were decreased, but the levels of cdk4, cdk6, cdk2, p16(INK4a), and p21(Cip1) were not affected. Among these effects, the decrease in cyclin D1 was prominent. DE decreased the level of cyclin D1 in rasREF cells in the suspension culture (a) at 0.1 muM and in the substratum-attached culture (b) at 1 muM, while the level of cyclin D1 in REF cells in the substratum-attached culture (c) was not decreased at 1 muM. The extent of growth inhibition correlated with the decrease in cyclin D1. The level of cyclin D1 mRNA of rasREF cells in the suspension culture (a) was also decreased by DE. DE decreased cyclin D1 mRNA, resulting in inhibition of anchorage-independent growth of rasREF cells.