p62/SQSTM1 is involved in caspase‐8 associated cell death induced by proteasome inhibitor MG132 in U87MG cells
p62/SQSTM1 is involved in caspase‐8 associated cell death induced by proteasome inhibitor MG132 in U87MG cells
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DOI：
10.1002/cbin.10311
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发表时间：
2014-10
影响因子：
3.9
通讯作者：
R. Zeng;Yi-bo Zhang;Yu Fan;Ge Wu
中科院分区：
文献类型：
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作者：
R. Zeng;Yi-bo Zhang;Yu Fan;Ge Wu
多形性胶质母细胞瘤（GBM）是最常见和致命的脑癌类型。蛋白酶体抑制剂作为一类新的抗胶质瘤药物正在兴起;然而，它们杀死恶性细胞的机制仍然不清楚。我们用蛋白酶体抑制剂MG 132处理U87 MG细胞，发现细胞死亡与caspase-8激活和自噬蛋白p62/SQSTM 1相关。为了探讨自噬和p62/SQSTM 1在MG 132诱导的癌细胞死亡中的作用，我们通过自噬抑制、自噬诱导或p62/SQSTM 1基因表达的变化来检测MG 132的细胞毒性。MG 132短期处理后自噬被激活，而自噬的抑制加剧了MG 132诱导的细胞死亡，随后是高水平的p62/SQSTM 1和活性caspase-8（p18）。此外，U87 MG细胞死亡依赖于p62/SQSTM 1，其功能需要其C末端乌巴结构域来减弱MG 132诱导的细胞死亡。结果表明，p62/SQSTM 1是一个潜在的贡献者，在确定的命运U87 MG细胞缺乏蛋白水解活性。
Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. Proteasome inhibitors are emerging as a new class of anti‐glioma agents; however, the mechanisms of their killing malignant cells are still unclear. We treated U87MG cells with the proteasome inhibitor MG132 and found that cell death correlated with caspase‐8 activation and autophagy protein p62/SQSTM1.To explore the role of autophagy and p62/SQSTM1 in MG132‐induced cancer cell death, we measured the alteration of MG132's cytotoxicity by autophagy inhibition, autophagy induction or variation of p62/SQSTM1 gene expression. Autophagy was activated upon MG132 treatment for short periods, while inhibition of autophagy aggravated MG132‐induced cell death followed by high levels of p62/SQSTM1 and active caspase‐8 (p18). Moreover, U87MG cell death was dependent on p62/SQSTM1, and its function required its C‐terminus UBA domain to attenuate the MG132‐induced cell death. The results suggest that p62/SQSTM1 is a potential contributor in determining the fate of U87MG cells deficient in proteolytic activity.