The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival.
The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival.
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DOI：
10.1038/cdd.2009.149
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发表时间：
2010-04
影响因子：
12.4
通讯作者：
Zeh HJ
中科院分区：
文献类型：
--
作者：
Kang R;Tang D;Schapiro NE;Livesey KM;Farkas A;Loughran P;Bierhaus A;Lotze MT;Zeh HJ
诱导的晚期糖基化终末产物受体（AGEs）的激活导致NF-κB和MAP激酶信号通路的启动，从而导致炎症的传播和持续。基因敲除动物对急性炎症和致癌物诱导的肿瘤发展较不敏感。我们已经报道，大多数形式的肿瘤细胞死亡导致释放的配体，HMGB 1。我们现在报道了一个新的作用，在肿瘤细胞对压力的反应。靶向敲低肿瘤细胞中的TNF-α导致细胞凋亡增加、自噬减少和肿瘤细胞存活减少。相比之下，过表达的p53与增强的自噬、减少的凋亡和更大的肿瘤细胞活力相关。p53依赖性线粒体途径限制细胞凋亡。此外，RAGE持续的自噬与mTOR磷酸化降低和Beclin-1/VPS 34自噬体形成增加相关。这些发现表明炎症受体在肿瘤细胞对应激的反应中起着迄今为止未被认识的作用。此外，这些研究建立了肿瘤微环境中的炎症介质与对程序性细胞死亡的抵抗之间的直接联系。我们的数据表明，靶向抑制cDNAs或其配体可能作为新的目标，以加强目前的癌症治疗。
Activation of the induced receptor for advanced glycation endproducts (RAGE) leads to initiation of NF-κB and MAP kinase signaling pathways resulting in propagation and perpetuation of inflammation. RAGE knock out animals are less susceptible to acute inflammation and carcinogen induced tumor development. We have reported that most forms of tumor cell death result in release of the RAGE ligand, HMGB1. We now report a novel role for RAGE in the tumor cell response to stress. Targeted knockdown of RAGE in the tumor cell, leads to increased apoptosis, diminished autophagy and decreased tumor cell survival . In contrast, overexpression of RAGE is associated with enhanced autophagy, diminished apoptosis and greater tumor cell viability. RAGE limits apoptosis through a p53 dependent mitochondrial pathway. Moreover, RAGE-sustained autophagy is associated with decreased phosphorylation of mTOR and increased Beclin-1/VPS34 autophagosome formation. These findings demonstrate that the inflammatory receptor RAGE plays a heretofore unrecognized role in the tumor cell response to stress. Furthermore, these studies establish a direct link between inflammatory mediators in the tumor microenvironment and resistance to programmed cell death. Our data suggest that targeted inhibition of RAGE or its ligands may serve as novel targets to enhance current cancer therapies.
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影响因子：
3.9
作者：
Fuentes, Maren K.;Nigavekar, Shraddha S.;Huang, Emina H.
通讯作者：
Huang, Emina H.
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
影响因子：
5.7
作者：
Fujii, Satoshi;Mitsunaga, Shuichi;Ochiai, Atsushi
通讯作者：
Ochiai, Atsushi
DOI：
10.1186/cc6164
发表时间：
2008
期刊：
Critical care (London, England)
影响因子：
--
作者：
Bopp C;Bierhaus A;Hofer S;Bouchon A;Nawroth PP;Martin E;Weigand MA
通讯作者：
Weigand MA
影响因子：
5.5
作者：
Ito, Norimasa;DeMarco, Richard A.;Lotze, Michael T.
通讯作者：
Lotze, Michael T.