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首页> 外文期刊>Cell cycle >Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells
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Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells

机译：Nf1缺陷细胞中PKC抑制诱导有丝分裂灾难

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Mutations of tumor suppressor Nf1 gene deregulate Ras-mediated signaling, which confers the predisposition for developing benign or malignant tumors. Inhibition of protein kinase C (PKC) was shown to be in synergy with aberrant Ras for the induction of apoptosis in various types of cancer cells. However, it has not been investigated whether loss of PKC is lethal for Nf1-deficient cells. In this study, using HMG (3-hydroxy-3-methylgutaryl, a PKC inhibitor), we demonstrate that the inhibition of PKC by HMG treatment triggered a persistently mitotic arrest, resulting in the occurrence of mitotic catastrophe in Nf1-deficient ST8814 cells. However, the introduction of the Nf1 effective domain gene into ST8814 cells abolished this mitotic crisis. In addition, HMG injection significantly attenuated the growth of the xenografted ST8814 tumors. Moreover, Chk1 was phosphorylated, accompanied with the persistent increase of cyclin B1 expression in HMG-treated ST8814 cells. The knockdown of Chk1 by the siRNA prevented the Nf1-deficient cells from undergoing HMG-mediated mitotic arrest as well as mitotic catastrophe. Thus, our data suggested that the suppression of PKC activates the Chk1-mediated mitotic exit checkpoint in Nf1-deficient cells, leading to the induction of apoptosis via mitotic catastrophe. Collectively, the study indicates that targeting PKC may be a potential option for developing new strategies to treat Nf1-deficiency-related diseases.
机译：肿瘤抑制因子Nf1基因的突变会解除Ras介导的信号转导，这赋予了其发展良性或恶性肿瘤的易感性。蛋白激酶C（PKC）的抑制作用与异常Ras协同作用，可诱导各种类型癌细胞的凋亡。但是，尚未研究过缺失Nf1的细胞是否会致死PKC。在这项研究中，使用HMG（3-羟基-3-甲基古塔基，一种PKC抑制剂），我们证明了HMG治疗对PKC的抑制触发了持续的有丝分裂阻滞，从而导致Nf1缺失的ST8814细胞发生有丝分裂灾难。但是，将Nf1有效域基因导入ST8814细胞消除了这种有丝分裂危机。另外，HMG注射显着减弱了异种移植的ST8814肿瘤的生长。此外，Chk1被磷酸化，伴随着HMG处理的ST8814细胞中细胞周期蛋白B1表达的持续增加。 siRNA抑制Chk1可以阻止Nf1缺陷细胞经历HMG介导的有丝分裂阻滞以及有丝分裂灾难。因此，我们的数据表明，PKC的抑制激活了Nf1缺陷细胞中Chk1介导的有丝分裂出口检查点，导致通过有丝分裂灾难诱导凋亡。总体而言，该研究表明，针对PKC可能是开发治疗Nf1缺乏症相关疾病的新策略的潜在选择。

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