Sulforaphane-cysteine downregulates CDK4 /CDK6 and inhibits tubulin polymerization contributing to cell cycle arrest and apoptosis in human glioblastoma cells.
Sulforaphane-cysteine downregulates CDK4 /CDK6 and inhibits tubulin polymerization contributing to cell cycle arrest and apoptosis in human glioblastoma cells.
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DOI：
10.18632/aging.103537
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发表时间：
2020-08-29
期刊：
影响因子：
--
通讯作者：
Wu W
中科院分区：
文献类型：
--
作者：
Li J;Zhou Y;Yan Y;Zheng Z;Hu Y;Wu W
本研究通过高效液相色谱-质谱/质谱（HPLC-MS/MS）和蛋白质组学分析证实，sulforaphan -半胱氨酸（SFN-Cys）调节U87MG细胞G0/G1和G2/M期细胞周期相关蛋白的表达。此外，通过TCGA和CGGA数据库分析，胶质母细胞瘤中CDK4、CDK6和α-微管蛋白mRNA产物明显高于正常组织，这些结果与病理分级和临床预后显著相关。此外，Western blot结果显示SFN-Cys以剂量依赖性方式下调CDK4、CDK6和p-Rb，这些结果在U87MG和U373MG细胞中被p-ERK1/2阻滞剂PD98059逆转。蛋白酶体抑制剂MG132逆转了CDK4、CDK6和p-Rb的减少；同样，SFN-Cys对26S蛋白酶体的上调被PD98059逆转。有趣的是，SFN-Cys通过磷酸化erk1 /2引起的蛋白酶体降解降低CDK4和CDK6，导致Rb磷酸化降低，从而在G0/G1期阻滞细胞周期。Western blot结果显示，SFN-Cys下调α-微管蛋白，导致微管断裂和聚集，细胞周期阻滞在G2/M期，细胞凋亡。这些结果可能有助于我们了解胶质母细胞瘤进展的分子病因，从而建立新的抗癌治疗方法。
Here we demonstrated that sulforaphane-cysteine (SFN-Cys) regulated cell cycle-related protein expressions in G0/G1 and G2/M phases of U87MG cells via High Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (HPLC-MS/MS) and proteomics analysis. Further, mRNA products of CDK4, CDK6 and α-tubulin were significantly higher in glioblastoma than those in normal tissues, and these results were significantly correlated to pathological grades and clinical prognosis via analyzing TCGA and CGGA databases. Furthermore, Western blot showed that SFN-Cys downregulated CDK4, CDK6 and p-Rb in a dose-dependent manner and these results were reversed by p-ERK1/2 blocker PD98059 in U87MG and U373MG cells. The reductions of CDK4, CDK6 and p-Rb were reversed by proteasome inhibitor MG132; similarly, the upregulation of 26S proteasome by SFN-Cys was reversed by PD98059. Interestingly, SFN-Cys decreased CDK4 and CDK6 by phosphorylated ERK1/2-caused proteasomal degradation resulting in decreased Rb phosphorylation contributing to cell cycle arrest in G0/G1 phase. Besides, Western blot showed that SFN-Cys downregulated α-tubulin resulting in microtubule disruption and aggregation, and cell cycle arrest in G2/M phase and apoptosis. These results might help us understand the molecular etiology of glioblastoma progression to establish brand-new anti-cancer therapies.
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