Circadian clock components RORα and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells.
Circadian clock components RORα and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells.
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昼夜节律时钟成分 RORalpha 和 Bmal1 介导 MLN4924 在骨肉瘤细胞中的抗增殖作用。
DOI：
10.18632/oncotarget.11807
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发表时间：
2016-10-04
期刊：
影响因子：
--
通讯作者：
Li JD
中科院分区：
文献类型：
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作者：
Zhang S;Zhang J;Deng Z;Liu H;Mao W;Jiang F;Xia Z;Li JD
抗癌小分子MLN4924是一种nedd8激活酶（NAE）抑制剂，可触发癌细胞的细胞周期阻滞、细胞凋亡和衰老。在本研究中，我们证明MLN4924通过诱导G2/M细胞周期阻滞和凋亡来抑制骨肉瘤细胞增殖。我们的研究结果表明，MLN4924通过降低其泛素化来稳定类视黄醇孤儿核受体α (RORα)。RNA干扰RORα可减弱MLN4924对U2OS骨肉瘤细胞的抗增殖作用。MLN4924上调rora的两个转录靶点p21和Bmal1的表达。然而，p21在MLN4924对U2OS骨肉瘤细胞的抗增殖作用中发挥的作用很小。相反，siRNA抑制Bmal1可减弱MLN4924在U2OS骨肉瘤细胞中的抗增殖作用，说明MLN4924介导的细胞生长抑制是由Bmal1介导的。这些结果表明，MLN4924是一种很有前景的骨肉瘤治疗药物，并提示MLN4924诱导的肿瘤生长抑制是由生物钟成分rora和Bmal1介导的。
The anticancer small molecule MLN4924, a Nedd8-activating enzyme (NAE) inhibitor, triggers cell-cycle arrest, apoptosis, and senescence in cancer cells. In this study, we demonstrate that MLN4924 suppresses osteosarcoma cell proliferation by inducing G2/M cell cycle arrest and apoptosis. Our results indicate that MLN4924 stabilizes the retinoid orphan nuclear receptor alpha (RORα) by decreasing its ubiquitination. RNA interference of RORα attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells. MLN4924 up-regulates the expression of p21 and Bmal1, two transcriptional targets of RORα. However, p21 plays a minimal role in the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells. In contrast, Bmal1 suppression by siRNA attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells, indicating that the MLN4924-mediated cell growth inhibition is mediated by Bmal1. These results show MLN4924 to be a promising therapeutic agent for the treatment of osteosarcoma and suggest that MLN4924-induced tumor growth inhibition is mediated by the circadian clock components RORα and Bmal1.