Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3β/CUX1 pathway
Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3β/CUX1 pathway
复制标题
组织蛋白酶 L 通过调节 GSK-3 beta/CUX1 通路促进电离辐射诱导的 U251 胶质瘤细胞迁移和侵袭
DOI：
10.1016/j.cellsig.2018.01.012
复制
发表时间：
2018-04-01
影响因子：
4.8
通讯作者：
Liang, Zhongqin
中科院分区：
文献类型：
--
作者：
Fei, Yao;Xiong, Yajie;Liang, Zhongqin
组织蛋白酶L（CTSL）是一种溶酶体半胱氨酸蛋白酶过表达并被肿瘤细胞分泌。我们先前的研究发现，CTSL参与了电离辐射（IR）诱导的上皮 - 间质转变（EMT）以及神经胶质瘤侵袭和迁移的增加。但是，CTSL促进这种IR诱导的神经胶质瘤迁移和侵袭的机制尚不清楚。在这项研究中，我们通过U251细胞中的CTSL介导的丝氨酸-9残基的CTSL介导的丝氨酸-9残基的磷酸化来证明IR降低的糖原合酶激酶-3β（GSK-3β）活性。此外，在过表达的CTSL细胞中抑制P-GSK-3β（SER9）减弱EMT并降低了蜗牛的表达，蜗牛是EMT相关的转录因子。结果，与过度CTSL细胞相比，U251细胞迁移和侵袭被抑制。或者，当CTSL被IR激活或外源性过度表达时，CTSL通过处理同源蛋白切割Like1（CUX1）来促进EMT，以产生生理活性的P110同工型。简而言之，这项研究表明，IR诱导的EMT以及神经胶质瘤细胞的迁移和侵袭是由CTSL通过AKT/GSK-3β/Snail和Cux1途径介导的。因此，这项研究还导致鉴定了胶质瘤治疗干预的潜在新靶标。
Cathepsin L (CTSL) is a lysosomal cysteine protease overexpressed and secreted by tumor cells. Our previous study found that CTSL was involved in ionizing radiation (IR)-induced epithelial-mesenchymal transition (EMT) and the increase of glioma invasion and migration. However, the mechanisms by which CTSL promoted this IR-induced glioma migration and invasion remained unclear. In this study, we demonstrated that IR-reduced glycogen synthase kinase-3 beta (GSK-3 beta) activity, via the CTSL-mediated phosphorylation of its serine-9 residue, in U251 cells. Moreover, inhibition of p-GSK-3 beta(ser9) in overexpressing CTSL cells attenuated EMT and decreased the expression of snail, an EMT-related transcription factor. As a result, U251 cell migration and invasion was inhibited compared to over-CTSL cells. Alternatively, when CTSL was activated by IR or exogenously over expressed, CTSL promoted EMT by processing homeobox protein cut-like1 (CUX1) to produce the physiologically active p110 isoform. In brief, this study revealed that IR-induced EMT as well as migration and invasion of glioma cells are mediated by CTSL through the Akt/GSK-3 beta/snail and CUX1 pathways. Consequently, this research also led to the identification of a potential novel target for therapeutic intervention of glioma.