The dual role of BI 2536, a small-molecule inhibitor that targets PLK1, in induction of apoptosis and attenuation of autophagy in neuroblastoma cells
The dual role of BI 2536, a small-molecule inhibitor that targets PLK1, in induction of apoptosis and attenuation of autophagy in neuroblastoma cells
复制标题
BI 2536 是一种针对 PLK1 的小分子抑制剂，具有诱导神经母细胞瘤细胞凋亡和减弱自噬的双重作用。
DOI：
10.7150/jca.33110
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Pan, Jian
中科院分区：
文献类型：
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作者：
Li, Zhiheng;Yang, Chun;Pan, Jian
神经母细胞瘤（NB）是儿童最常见的颅外实体瘤，5年生存率不到40%。Polo样激酶1（PLK 1）是一种丝氨酸/苏氨酸蛋白激酶，在有丝分裂期间表达，并在多种癌症中过度表达，包括神经母细胞瘤。我们发现PLK 1的高表达与NB患者的不良预后有关。BI 2536是一种针对PLK 1的小分子抑制剂，可显著降低一组NB细胞系中的细胞活力，IC 50小于100 nM。BI 2536处理的PLK 1抑制诱导NB细胞的细胞周期停滞在G（2）/M期和细胞凋亡。实时荧光定量PCR芯片显示PLK 1抑制相关基因，如BIRC 7、TNFSF 10、LGALS 1和DAD 1等。NB细胞中BI 2536处理增加了LC 3 - 1 I斑点形成和LC 3-II表达。通过透射电子显微镜观察BI 2536诱导的自噬体形成。然而，BI 2536通过降低SQSTM 1/p62表达和AMPK α（T172）磷酸化来消除NB细胞中的自噬通量。这些结果为BI 2536诱导细胞死亡的分子机制提供了新的线索，并提示BI 2536可能作为神经母细胞瘤的新候选药物。
Neuroblastoma (NB) is the most common extra-cranial solid tumor in childhood with the overall 5 years' survival less than 40%. Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and over expressed in multiple cancers, including neuroblastoma. We found that higher PLK1 expression related to poor outcome of NB patients. BI2536, a small molecule inhibitor against PLK1, significantly reduced cell viability in a panel of NB cell lines, with IC50 less than 100 nM. PLK1 inhibition by BI 2536 treatment induced cell cycle arrest at G(2)/M phase and cell apoptosis in NB cells. Realtime PCR array revealed the PLK1 inhibition related genes, such as BIRC7, TNFSF10, LGALS1 and DAD1 et al. Moreover, autophagy activity was investigated in the NB cells treated with BI 2536. BI 2536 treatment in NB cells increased LC3-1I puncta formation and LC3-II expression. Formation of autophagosome induced by BI 2536 was observed by transmission electron microscopy. However, BI2536 abrogated the autophagic flux in NB cells by reducing SQSTM1/p62 expression and AMPK alpha(T172) phosphorylation. These results provide new clues for the molecular mechanism of cell death induced by BI 2536 and suggest that BI 2536 may act as new candidate drug for neuroblastoma.