Effects of the kava chalcone flavokawain A differ in bladder cancer cells with wild-type versus mutant p53.
Effects of the kava chalcone flavokawain A differ in bladder cancer cells with wild-type versus mutant p53.
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DOI：
10.1158/1940-6207.capr-08-0165
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Zi X
中科院分区：
文献类型：
--
作者：
Tang Y;Simoneau AR;Xie J;Shahandeh B;Zi X
Flavokawain A 是卡瓦提取物中的主要查尔酮。我们评估了黄酮川蛋白 A 对细胞周期调节的作用机制。在 p53 野生型、低级别和乳头状膀胱癌细胞系 (RT4) 中，黄素卡因 A 增加 p21/WAF1 和 p27/KIP1，从而导致细胞周期蛋白依赖性激酶 2 (CDK2) 激酶活性降低以及随后的 G1 期停滞。 p21/WAF1蛋白的增加对应于mRNA水平的增加，而p27/KIP1积累与SKP2的下调相关，从而增加了p27/KIP1蛋白的稳定性。 p21/WAF1 和 p27/KIP1 的积累与细胞周期位置无关，因此不是细胞周期停滞的结果。相比之下，黄素卡因 A 在六种 p53 突变型高级别膀胱癌细胞系（T24、UMUC3、TCCSUP、5637、HT1376 和 HT1197）中诱导 G2-M 停滞。 Flavokawain A 显着降低 CDK1 抑制激酶 Myt1 和 Wee1 的表达，并引起细胞周期蛋白 B1 蛋白积累，导致 T24 细胞中 CDK1 激活。 RT4细胞中小干扰RNA抑制p53表达可恢复Cdc25C表达并下调p21/WAF1表达，从而使Cdc25C和CDK1激活，然后导致G2-M停滞和黄素卡因A增强的生长抑制作用。同样，黄卡素A还在p53敲除中引起显着的CDK1激活和G2-M停滞，但在p53中则不然野生型HCT116细胞。黄素卡因 A 在 p53 缺陷细胞中诱导 G2-M 期停滞的选择性值得进一步研究，作为预防和治疗膀胱癌的新机制。
Flavokawain A is the predominant chalcone from kava extract. We have assessed the mechanisms of flavokawain A's action on cell cycle regulation. In a p53 wild-type, low-grade, and papillary bladder cancer cell line (RT4), flavokawain A increased p21/WAF1 and p27/KIP1, which resulted in a decrease in cyclin-dependent kinase-2 (CDK2) kinase activity and subsequent G1 arrest. The increase of p21/WAF1 protein corresponded to an increased mRNA level, whereas p27/KIP1 accumulation was associated with the down-regulation of SKP2 and then increased the stability of the p27/KIP1 protein. The accumulation of p21/WAF1 and p27/KIP1 was independent of cell cycle position and thus not a result of the cell cycle arrest. In contrast, flavokawain A induced a G2-M arrest in six p53 mutant-type, high-grade bladder cancer cell lines (T24, UMUC3, TCCSUP, 5637, HT1376, and HT1197). Flavokawain A significantly reduced the expression of CDK1-inhibitory kinases, Myt1 and Wee1, and caused cyclin B1 protein accumulation leading to CDK1 activation in T24 cells. Suppression of p53 expression by small interfering RNA in RT4 cells restored Cdc25C expression and down-regulated p21/WAF1 expression, which allowed Cdc25C and CDK1 activation and then led to a G2-M arrest and an enhanced growth-inhibitory effect by flavokawain A. Consistently, flavokawain A also caused a pronounced CDK1 activation and G2-M arrest in p53 knockout but not in p53 wild-type HCT116 cells. This selectivity of flavokawain A for inducing a G2-M arrest in p53-defective cells deserves further investigation as a new mechanism for the prevention and treatment of bladder cancer.