Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors
Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors
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DOI：
10.1038/sj.onc.1209112
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发表时间：
2006-02-01
期刊：
影响因子：
8
通讯作者：
Kalpana, GV
中科院分区：
文献类型：
--
作者：
Alarcon-Vargas, D;Zhang, Z;Kalpana, GV
横纹肌样瘤（RT）是侵袭性的，目前无法治愈的儿科恶性肿瘤。INI1/hSNF5是RT中双等位基因失活的肿瘤抑制因子。我们以前的研究表明，细胞周期蛋白D1是一个关键的下游目标INI1/hSNF5和发生和/或生存的RT在体内是严重依赖于细胞周期蛋白D1的存在。在这份报告中，我们已经测试的假设，治疗靶向细胞周期蛋白D1是一种有效的手段治疗RT。我们发现，RNA干扰细胞周期蛋白D1在横纹肌样细胞是足以诱导G1期阻滞和凋亡。此外，我们发现用低微摩尔浓度的N-（4-羟苯基）维甲酰胺（4-HPR）进行药理干预（下调细胞周期蛋白D1）可诱导横纹肌样细胞系的G1期阻滞和细胞凋亡。4-HPR与4-羟基-他莫昔芬（4OH-Tam）组合，协同抑制横纹肌样细胞的存活以及锚定依赖性和非依赖性生长，并引起细胞周期阻滞和凋亡的协同诱导。4-HPR和他莫昔芬在体内异种移植模型中表现出协同的RT生长抑制作用。在体外和体内肿瘤模型中，药物组合的作用与细胞周期蛋白D1水平的耗竭相关。这些结果表明，4-HPR和他莫昔芬是RT的有效化疗药物。我们认为下调细胞周期蛋白D1是一种新的有效的治疗RT的策略。
Rhabdoid tumors (RTs) are aggressive and currently incurable pediatric malignancies. INI1/hSNF5 is a tumor suppressor biallelically inactivated in RTs. Our previous studies have indicated that cyclin D1 is a key downstream target of INI1/hSNF5 and genesis and/or survival of RTs in vivo is critically dependent on the presence of cyclin D1. In this report, we have tested the hypothesis that therapeutic targeting of cyclin D1 is an effective means of treating RTs. We found that RNA interference of cyclin D1 in rhabdoid cells was sufficient to induce G1 arrest and apoptosis. Furthermore, we found that pharmacological intervention with low micromolar concentrations of N-(4-hydroxyphenyl) retinamide (4-HPR), which downmodulates cyclin D1, induced G1 arrest and apoptosis in rhabdoid cell lines. 4-HPR in combination with 4-hydroxy-tamoxifen (4OH-Tam), synergistically inhibited survival as well as anchorage-dependent and -independent growth of rhabdoid cells and caused synergistic induction of cell cycle arrest and apoptosis. 4-HPR and tamoxifen exhibited synergistic growth inhibition of RTs in xenograft models in vivo. The effects of combination of drugs were correlated to the depletion of cyclin D1 levels both in in vitro and in vivo tumor models. These results demonstrate that 4-HPR and tamoxifen are effective chemotherapeutic agents for RTs. We propose that downmodulation of cyclin D1 is a novel and effective therapeutic strategy for RTs.