An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cells.
An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cells.
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DOI：
10.1111/cas.12396
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发表时间：
2014-05
期刊：
影响因子：
5.7
通讯作者：
Sasano H
中科院分区：
文献类型：
--
作者：
Nihira K;Miki Y;Ono K;Suzuki T;Sasano H
p62/SQSTM1 （p62）是一种涉及多种信号转导途径的多功能蛋白，可通过自噬选择性降解，自噬是蛋白和细胞器的溶酶体降解过程。最近也有报道称P62在多种恶性肿瘤中过表达并抑制癌细胞增殖。然而，它与癌细胞自噬的关系在很大程度上仍然未知。因此，在本研究中，我们检测了p62抑制对p62阳性癌细胞自噬和细胞存活调节的影响。p62沉默显著抑制表达p62的PC9和A549细胞的增殖和诱导自噬。电镜分析显示p62沉默导致自噬体形成多层膜。P62沉默介导的细胞活力降低可以通过基因组和药理学抑制自噬而非凋亡来恢复。这些发现也在包括腺癌和鳞状细胞癌在内的几种类型的癌细胞系中检测到。我们目前的研究结果表明，抑制p62可导致具有多层膜的自噬体的形成和自噬细胞的死亡，因此p62可以成为抗肿瘤药物开发的一个有吸引力的靶点。
p62/SQSTM1 (p62) is a multifunctional protein implicated in several signal transduction pathways and selectively degraded by autophagy, a process for lysosomal degradation of both protein and organelle. p62 was also recently reported to be overexpressed in various malignancies and its inhibition to suppress carcinoma cell proliferation. However, its correlation with autophagy in carcinoma cells has remained largely unknown. Therefore, in this study, we examined the effects of p62 inhibition on the regulation of autophagy and cell survival in p62-positive carcinoma cells. p62-silencing dramatically suppressed cell proliferation and induced autophagy in p62 expressing PC9 and A549 cells. Electron microscopical analysis revealed the formation of autophagosomes with multilayer membranes caused by p62-silencing. p62 silencing-mediated reduced cell viability was restored by both genomic and pharmacological inhibition of autophagy but not that of apoptosis. These findings were also detected in several types of carcinoma cell lines including adenocarcinomas and squamous cell carcinomas. Results of our present study revealed that an inhibition of p62 resulted in the formation of mis-regulated autophagosomes with multilayer membranes and an autophagic cell death, and p62 can therefore be an attractive target for the development of anti-neoplastic agents.
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影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
50.3
作者：
Duran, Angeles;Linares, Juan F.;Moscat, Jorge
通讯作者：
Moscat, Jorge
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
影响因子：
8.6
作者：
Su, YX;Qian, HL;Peng, XX
通讯作者：
Peng, XX