A Peptidic Unconjugated GRP78/BiP Ligand Modulates the Unfolded Protein Response and Induces Prostate Cancer Cell Death
A Peptidic Unconjugated GRP78/BiP Ligand Modulates the Unfolded Protein Response and Induces Prostate Cancer Cell Death
复制标题
DOI：
10.1371/journal.pone.0045690
复制
发表时间：
2012-10-01
期刊：
影响因子：
3.7
通讯作者：
Cato, Andrew C. B.
中科院分区：
文献类型：
--
作者：
Maddalo, Danilo;Neeb, Antje;Cato, Andrew C. B.
分子伴侣GRP 78/BiP是内质网中蛋白质折叠的关键调节因子，并且其在癌细胞存活和化学抗性中起关键作用。因此，抑制其功能已成为癌症治疗中抑制肿瘤细胞生长的重要策略。先前实现这一目标的努力已经使用了与前药或细胞死亡诱导序列缀合的结合GRP 78/BiP的肽。在这里，我们描述了一种肽，诱导前列腺肿瘤细胞死亡，而不需要任何共轭序列。该肽是衍生自辅伴侣Bag-1的序列。我们已经表明，该序列与GRP 78/BiP相互作用并抑制其重折叠活性。此外，我们已经证明，它调节未折叠的蛋白质在ER应激反应，导致PARP和caspase-4裂解。稳定表达该肽的前列腺癌细胞在体内异种移植肿瘤模型中显示生长减少和凋亡增加。破坏Bag-1肽与GRP 78/BiP结合或下调GRP 78表达的氨基酸取代损害了该肽的抑制作用。因此，该序列代表用于抗肿瘤治疗的候选前导肽。
The molecular chaperone GRP78/BiP is a key regulator of protein folding in the endoplasmic reticulum, and it plays a pivotal role in cancer cell survival and chemoresistance. Inhibition of its function has therefore been an important strategy for inhibiting tumor cell growth in cancer therapy. Previous efforts to achieve this goal have used peptides that bind to GRP78/BiP conjugated to pro-drugs or cell-death-inducing sequences. Here, we describe a peptide that induces prostate tumor cell death without the need of any conjugating sequences. This peptide is a sequence derived from the cochaperone Bag-1. We have shown that this sequence interacts with and inhibits the refolding activity of GRP78/BiP. Furthermore, we have demonstrated that it modulates the unfolded protein response in ER stress resulting in PARP and caspase-4 cleavage. Prostate cancer cells stably expressing this peptide showed reduced growth and increased apoptosis in in vivo xenograft tumor models. Amino acid substitutions that destroyed binding of the Bag-1 peptide to GRP78/BiP or downregulation of the expression of GRP78 compromised the inhibitory effect of this peptide. This sequence therefore represents a candidate lead peptide for anti-tumor therapy.