Responses in mantle cell lymphoma cells to SNS-032 depend on the biological context of each cell line.
Responses in mantle cell lymphoma cells to SNS-032 depend on the biological context of each cell line.
复制标题
DOI：
10.1158/0008-5472.can-09-3578
复制
发表时间：
2010-08-15
期刊：
影响因子：
11.2
通讯作者：
Plunkett W
中科院分区：
文献类型：
--
作者：
Chen R;Chubb S;Cheng T;Hawtin RE;Gandhi V;Plunkett W
SNS-032 是调节细胞周期和转录的细胞周期蛋白依赖性激酶 (Cdk) 2、7 和 9 的有效抑制剂。我们对惰性原发性慢性淋巴细胞白血病细胞的研究表明，SNS-032 抑制转录、减少抗凋亡蛋白 Mcl-1 并诱导细胞凋亡。本研究的重点是在四种增殖性套细胞淋巴瘤 (MCL) 系（Jeko-1、Granta 519、Mino 和 SP-53）中评估该化合物。与其针对 Cdk9 和 Cdk7 的作用一致，SNS-032 抑制所有 4 个细胞系中 RNA pol II 的磷酸化并阻断 RNA 合成。短寿命蛋白的转录物和蛋白水平下降，包括细胞周期蛋白 D1 和 Mcl-1。所有细胞系中的细胞生长均以浓度依赖性方式受到抑制。在 JeKo-1、Mino 和 SP-53 细胞中诱导细胞凋亡，而不会破坏细胞周期分布。然而，Granta 细胞中的细胞凋亡有限；相反，克隆存活率显着降低。 SiRNA 用于特异性敲低 JeKo-1 和 Granta 细胞中的 Mcl-1 和细胞周期蛋白 D1。敲低 Mcl-1 会诱导 Jeko-1 细胞显着凋亡，但不会诱导 Granta 细胞凋亡。减少细胞周期蛋白 D1 而不是 Mcl-1 与 Granta 细胞克隆形成存活的丧失相关。因此，这些结果表明 MCL 细胞系具有独特的维持其生存的机制，并且 SNS-032 的作用机制取决于单个细胞系的生物学背景。
SNS-032 is a potent inhibitor of cyclin-dependent kinases (Cdk) 2, 7 and 9 that regulate the cell cycle and transcription. Our studies in indolent primary chronic lymphocytic leukemia cells demonstrated that SNS-032 inhibited transcription, diminished the anti-apoptotic protein Mcl-1, and induced apoptosis. The present study focuses on evaluating this compound in four proliferating mantle cell lymphoma (MCL) lines (Jeko-1, Granta 519, Mino and SP-53). Consistent with its action against Cdk9 and Cdk7, SNS-032 inhibited the phosphorylation of RNA pol II in all 4 lines and blocked RNA synthesis. The transcripts and protein levels of short-lived proteins decreased, including cyclin D1 and Mcl-1. Cell growth was inhibited in a concentration-dependent manner in all lines. Apoptosis was induced in JeKo-1, Mino and SP-53 cells without disrupting cell cycle distribution. However, apoptosis was limited in Granta cells; rather, there was a significant reduction of clonogenic survival. SiRNA was used to specifically knock down Mcl-1 and cyclin D1 in JeKo-1 and Granta cells. Knocking down Mcl-1 induced significant apoptosis in Jeko-1 cells but not Granta cells. Reducing cyclin D1, rather than Mcl-1 was associated with loss of clonogenic survival in Granta cells. Thus, these results indicated that MCL cell lines have distinct mechanisms sustaining their survival, and the mechanism of action SNS-032 is dependent on the biological context of an individual line.