Autophagy protein p62/SQSTM1 is involved in HAMLET-induced cell death by modulating apotosis in U87MG cells.
Autophagy protein p62/SQSTM1 is involved in HAMLET-induced cell death by modulating apotosis in U87MG cells.
复制标题
DOI：
10.1038/cddis.2013.77
复制
发表时间：
2013-03-21
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
哈姆雷特是油酸和脱钙α-乳清蛋白的复合物，被发现在体外和体内选择性地杀死肿瘤细胞。自噬是药物诱导胶质瘤细胞死亡的重要细胞过程。我们用哈姆雷特处理U87 MG人脑胶质瘤细胞，发现细胞活力明显下降，并伴有自噬激活。有趣的是，我们观察到哈姆雷特短时间处理后，自噬体酶的重要底物p62/SQSTM 1在蛋白质水平上增加。为了更好地理解自噬和p62/SQSTM 1在HAMLET诱导的细胞死亡中的功能，我们用生化或遗传方法调节自噬或p62/SQSTM 1的水平。结果表明，自噬的抑制加剧了HAMLET诱导的细胞死亡，而自噬的激活减弱了这一过程。同时，我们发现野生型p62/SQSTM 1的过表达能够激活caspase-8，从而促进HAMLET诱导的细胞凋亡，而p62/SQSTM 1的敲低表现出相反的效果。我们进一步证明了哈姆雷特处理后p62/SQSTM 1的功能需要其C-末端乌巴结构域。我们的研究结果表明，除了在HAMLET处理的胶质瘤细胞自噬激活的标志物，p62/SQSTM 1也可以作为一个重要的介导激活caspase-8依赖的细胞死亡。
HAMLET is a complex of oleic acids and decalcified α-lactalbumin that was discovered to selectively kill tumor cells both in vitro and in vivo. Autophagy is an important cellular process involved in drug-induced cell death of glioma cells. We treated U87MG human glioma cells with HAMLET and found that the cell viability was significantly decreased and accompanied with the activation of autophagy. Interestingly, we observed an increase in p62/SQSTM1, an important substrate of autophagosome enzymes, at the protein level upon HAMLET treatment for short periods. To better understand the functionality of autophagy and p62/SQSTM1 in HAMLET-induced cell death, we modulated the level of autophagy or p62/SQSTM1 with biochemical or genetic methods. The results showed that inhibition of autophagy aggravated HAMLET-induced cell death, whereas activation of authophagy attenuated this process. Meanwhile, we found that overexpression of wild-type p62/SQSTM1 was able to activate caspase-8, and then promote HAMLET-induced apoptosis, whereas knockdown of p62/SQSTM1 manifested the opposite effect. We further demonstrated that the function of p62/SQSTM1 following HAMLET treatment required its C-terminus UBA domain. Our results indicated that in addition to being a marker of autophagy activation in HAMLET-treated glioma cells, p62/SQSTM1 could also function as an important mediator for the activation of caspase-8-dependent cell death.
登录
查看更多内容
影响因子：
11.2
作者：
Hu YL;DeLay M;Jahangiri A;Molinaro AM;Rose SD;Carbonell WS;Aghi MK
通讯作者：
Aghi MK
DOI：
10.1016/j.bbrc.2008.08.127
发表时间：
2008-11-07
影响因子：
3.1
作者：
Kamijima, Tatsuro;Ohmura, Ayaka;Demura, Makoto
通讯作者：
Demura, Makoto
影响因子：
6.4
作者：
Aits, Sonja;Gustafsson, Lotta;Svanborg, Catharina
通讯作者：
Svanborg, Catharina
影响因子：
3.7
作者：
Mercer N;Ramakrishnan B;Boeggeman E;Qasba PK
通讯作者：
Qasba PK
DOI：
10.1007/978-0-387-74087-4_8
发表时间：
2008-01-01
期刊：
BIOACTIVE COMPONENTS OF MILK
影响因子：
--
作者：
Hallgren, Oskar;Aits, Sonja;Svanborg, Catharina
通讯作者：
Svanborg, Catharina