Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4.
Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4.
复制标题
DOI：
10.1158/0008-5472.can-12-3212
复制
发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Rangnekar VM
中科院分区：
文献类型：
--
作者：
Burikhanov R;Shrestha-Bhattarai T;Qiu S;Shukla N;Hebbar N;Lele SM;Horbinski C;Rangnekar VM
肿瘤抑制因子PAR-4部分通过调节对凋亡的敏感性起作用，但其活性的基础尚不完全清楚。在这项研究中，我们描述了一种新的机制，抗凋亡的NF-κ B，揭示了它可以阻止PAR-4介导的凋亡，下调运输的PAR-4受体GRP 78从内质网（ER）的细胞表面。机制研究表明，NF-kappaB通过上调UACA（某些疾病环境中的促炎蛋白）的表达来介导这种抗凋亡机制。在癌症的临床标本中，相对于正常组织，NF-κ B活性和UACA表达之间存在强相关性。UACA在不同的癌细胞中与细胞内PAR-4结合，在那里它阻止GRP 78从ER易位到细胞表面。这种抗凋亡途径可以通过抑制NF-κ B或UACA表达水平来抑制，这增强了ER应激并恢复了GRP 78向细胞表面的运输，从而使癌细胞对细胞外PAR-4或GRP 78激动性抗体引起的凋亡敏感。总之，我们的研究结果确定了一种新的细胞内凋亡途径，由NF-κ B通过UACA升高介导，通过减弱ER应激和GRP 78易位到细胞表面可以减弱癌细胞对凋亡的敏感性。
Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of anti-apoptosis by NF-kappaB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum (ER) to the cell surface. Mechanistic investigations revealed that NF-kappaB mediated this anti-apoptotic mechanism by upregulating expression of UACA, a pro-inflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-kappaB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the ER to the cell surface. This pathway of anti-apoptosis could be inhibited by suppressing levels of NF-kappaB or UACA expression, which enhanced ER stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-kappaB through UACA elevation, which by attenuating ER stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis.