Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin
Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin
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DOI：
10.1152/ajpgi.00248.2006
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发表时间：
2007-01-01
影响因子：
4.5
通讯作者：
Park, Jung H. Y.
中科院分区：
文献类型：
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作者：
Lim, Do Y.;Jeong, Yoonhwa;Park, Jung H. Y.
木犀草素是在芹菜、青椒和紫苏叶中发现的 3',4',5,7-四羟基黄酮，可抑制动物模型中的肿瘤发生。我们研究了木犀草素介导的 HT-29 人结肠癌细胞系细胞周期进程和细胞凋亡的调节。木犀草素以浓度依赖性方式减少 DNA 合成和存活 HT-29 细胞数量。它抑制细胞周期蛋白依赖性激酶 (CDK) 4 和 CDK2 活性，导致 G(1) 阻滞，同时视网膜母细胞瘤蛋白磷酸化减少。木犀草素处理后2 h内CDK4和CDK2活性下降，其中40 μmol/l木犀草素处理细胞中CDK2活性下降38%（P < 0.05）。木犀草素抑制无细胞系统中的 CDK2 活性，表明它直接抑制 CDK2。木犀草素处理后，细胞周期蛋白 D-1 水平下降，但未检测到细胞周期蛋白 A、细胞周期蛋白 E、CDK4 或 CDK2 表达的变化。木犀草素还通过下调细胞周期蛋白 B-1 表达和抑制细胞分裂周期 (CDC)2 活性，促进治疗 24 小时后 G(2)/M 期阻滞。木犀草素通过增加半胱天冬酶 3、7 和 9 的活化以及增强聚 (ADP-核糖) 聚合酶裂解并降低 p21(CIP1/WAF1)、生存素、Mcl-1、Bcl-x(L) 和 Mdm-2 的表达来促进细胞凋亡。这些关键抗凋亡蛋白表达的减少可能导致 HT-29 细胞中观察到的 p53 依赖性细胞凋亡增加。我们证明木犀草素可促进 HT-29 结肠癌细胞系的细胞周期停滞和细胞凋亡，从而深入了解其抗肿瘤活性的机制。
Luteolin is 3', 4', 5,7-tetrahydroxyflavone found in celery, green pepper, and perilla leaf that inhibits tumorigenesis in animal models. We examined luteolin-mediated regulation of cell cycle progression and apoptosis in the HT-29 human colon cancer cell line. Luteolin decreased DNA synthesis and viable HT-29 cell numbers in a concentration-dependent manner. It inhibited cyclin-dependent kinase (CDK) 4 and CDK2 activity, resulting in G(1) arrest with a concomitant decrease of phosphorylation of retinoblastoma protein. Activities of CDK4 and CDK2 decreased within 2 h after luteolin treatment, with a 38% decrease in CDK2 activity (P < 0.05) observed in cells treated with 40 mu mol/l luteolin. Luteolin inhibited CDK2 activity in a cell-free system, suggesting that it directly inhibits CDK2. Cyclin D-1 levels decreased after luteolin treatment, although no changes in expression of cyclin A, cyclin E, CDK4, or CDK2 were detected. Luteolin also promoted G(2)/M arrest at 24 h posttreatment by downregulating cyclin B-1 expression and inhibiting cell division cycle (CDC)2 activity. Luteolin promoted apoptosis with increased activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and decreased expression of p21(CIP1/WAF1), survivin, Mcl-1, Bcl-x(L), and Mdm-2. Decreased expression of these key antiapoptotic proteins could contribute to the increase in p53-independent apoptosis that was observed in HT-29 cells. We demonstrate that luteolin promotes both cell cycle arrest and apoptosis in the HT-29 colon cancer cell line, providing insight about the mechanisms underlying its antitumorigenic activities.