Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug.
Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug.
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DOI：
10.3892/ijo.2015.3037
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发表时间：
2015-08
影响因子：
5.2
通讯作者：
Sen S
中科院分区：
文献类型：
--
作者：
Wang J;Yin H;Panandikar A;Gandhi V;Sen S
耐药性是转移性癌症系统治疗成功的主要障碍。我们分析了细胞周期调节蛋白在引起对N（膦酰基乙酰基）-L-天冬氨酸（PALA），从头嘧啶合成的抑制剂，在两个转移性的人癌细胞系MDA-MB-435的变种，分别从肺（L-2）和脑（Br-1）在裸鼠，引起的反应。L-2和Br-1细胞对PALA的敏感性有显著差异。虽然两种细胞类型显示初始S期延迟/停滞，Br-1细胞增殖，但大多数L-2细胞发生凋亡。PALA处理的L-2细胞发生凋亡时，细胞周期蛋白A（cyclinA）和磷酸化的Rb蛋白表达明显升高，同时bcl-2蛋白表达降低。在这些L-2细胞中检测到显著升高的细胞周期蛋白A相关和cdk 2激酶活性以及增加的E2 F1-DNA结合。诱导的异位细胞周期蛋白A表达通过激活凋亡途径使Br-1细胞对PALA敏感。我们的研究结果表明，细胞周期蛋白A和相关激酶的表达升高，可以激活暴露于DNA抗代谢物的细胞凋亡途径。消除这一途径可导致人类癌细胞的转移性变体对这些药物产生耐药性。
Drug resistance is a major obstacle in successful systemic therapy of metastatic cancer. We analyzed the involvement of cell cycle regulatory proteins in eliciting response to N (phosphonoacetyl)-L-aspartate (PALA), an inhibitor of de novo pyrimidine synthesis, in two metastatic variants of human cancer cell line MDA-MB-435 isolated from lung (L-2) and brain (Br-1) in nude mouse, respectively. L-2 and Br-l cells markedly differed in their sensitivity to PALA. While both cell types displayed an initial S phase delay/arrest, Br-l cells proliferated but most L-2 cells underwent apoptosis. There was distinct elevation in cyclin A, and phosphorylated Rb proteins concomitant with decreased expression of bcl-2 protein in the PALA treated L-2 cells undergoing apoptosis. Markedly elevated cyclin A associated and cdk2 kinase activities together with increased E2F1-DNA binding were detected in these L-2 cells. Induced ectopic cyclin A expression sensitized Br-l cells to PALA by activating an apoptotic pathway. Our findings demonstrate that elevated expression of cyclin A and associated kinase can activate an apoptotic pathway in cells exposed to DNA antimetabolites. Abrogation of this pathway can lead to resistance against these drugs in metastatic variants of human carcinoma cells.