Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop A ROLE FOR SECRETED PROSTATE-SPECIFIC ANTIGEN
Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop A ROLE FOR SECRETED PROSTATE-SPECIFIC ANTIGEN
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DOI：
10.1074/jbc.m110.129767
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发表时间：
2011-01-14
影响因子：
4.8
通讯作者：
Pizzo, Salvatore V.
中科院分区：
文献类型：
--
作者：
Misra, Uma K.;Payne, Sturgis;Pizzo, Salvatore V.
GRP 78是内质网中的一种特征性分子伴侣，对未折叠蛋白质反应至关重要。最近，它已被确定在细胞表面，在那里它有许多作用。在癌细胞上，它作为与促增殖/抗凋亡和促迁移机制偶联的信号受体发挥作用。在目前的研究中，我们证明了前列腺癌细胞表面GRP 78通过其天然配体活化的α（2）-巨球蛋白（α M-2*）的连接，导致前列腺特异性抗原（PSA）的合成上调2-3倍。PSA作为活性蛋白酶分泌到培养基中，在那里它与天然α M-2结合。所得的α M-2.PSA复合物与GRP 78结合，导致MEK 1/2、ERK 1/2、S6 K和Akt的活化增加1.5-2倍，这与DNA和蛋白质合成增加2-3倍相结合。PSA是前列腺癌进展的标志物，但其在疾病中的机制作用尚不清楚。目前的研究表明，PSA可能参与了一个依赖于信号转导的反馈回路，从而促进了人类前列腺癌细胞更具侵略性的行为。
GRP78, a well characterized chaperone in the endoplasmic reticulum, is critical to the unfolded protein response. More recently, it has been identified on the cell surface, where it has many roles. On cancer cells, it functions as a signaling receptor coupled to proproliferative/antiapoptotic and promigratory mechanisms. In the current study, we demonstrate that ligation of prostate cancer cell surface GRP78 by its natural ligand, activated alpha(2)-macroglobulin (alpha M-2*), results in a 2-3-fold up-regulation in the synthesis of prostate-specific antigen (PSA). The PSA is secreted into the medium as an active proteinase, where it binds to native alpha M-2. The resultant alpha M-2.PSA complexes bind to GRP78, causing a 1.5-2-fold increase in the activation of MEK1/2, ERK1/2, S6K, and Akt, which is coupled with a 2-3-fold increase in DNA and protein synthesis. PSA is a marker for the progression of prostate cancer, but its mechanistic role in the disease is unclear. The present studies suggest that PSA may be involved in a signal transduction-dependent feedback loop, whereby it promotes a more aggressive behavior by human prostate cancer cells.