Proapoptotic Cyclic Peptide BC71 Targets Cell-Surface GRP78 and Functions as an Anticancer Therapeutic in Mice.
Proapoptotic Cyclic Peptide BC71 Targets Cell-Surface GRP78 and Functions as an Anticancer Therapeutic in Mice.
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DOI：
10.1016/j.ebiom.2018.06.004
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发表时间：
2018-07
期刊：
影响因子：
11.1
通讯作者：
Ge R
中科院分区：
文献类型：
--
作者：
Kao C;Chandna R;Ghode A;Dsouza C;Chen M;Larsson A;Lim SH;Wang M;Cao Z;Zhu Y;Anand GS;Ge R
葡萄糖调节蛋白78（Glucose regulated protein 78 kDa，GRP 78）是近年来发现的肿瘤治疗靶点和肿瘤预后的生物标志物。在许多类型的癌症中观察到GRP 78的过表达，细胞表面GRP 78优先存在于癌细胞和癌血管内皮细胞中。Isthmin（ISM）是一种分泌的高亲和力促凋亡蛋白配体，与细胞表面GRP 78结合，可抑制小鼠血管生成和肿瘤生长。ISM的C-末端AMOP（MUC 4和其他蛋白中的粘附相关结构域）结构域在介导其与人脐静脉内皮细胞（HUVECs）的相互作用中至关重要。在这项工作中，我们报告了新的环肽窝藏的RKD基序在ISM的AMOP结构域的功能作为细胞表面GRP 78的促凋亡配体。最有效的肽BC 71与GRP 78结合并聚集到小鼠中的肿瘤。静脉内施用BC 71作为单一药剂抑制小鼠中的异种移植肿瘤生长，肿瘤血管生成显著减少并且细胞凋亡激增。荧光标记的BC 71通过靶向细胞表面GRP 78在小鼠肿瘤中积累。我们发现BC 71通过细胞表面GRP 78触发细胞凋亡，并激活HUVEC中的caspase-8和p53信号通路。使用酰胺氢-氘交换质谱（HDXMS），我们鉴定了BC 71优先通过GRP 78的氨基酸残基244-257与ATP结合的GRP 78结合。因此，BC 71作为进一步开发靶向细胞表面GRP 78的拟肽抗癌药物以及用于癌症预后的PET成像剂的有价值的原型。
Glucose regulated protein 78 kDa (GRP78) is a recently emerged target for cancer therapy and a biomarker for cancer prognosis. Overexpression of GRP78 is observed in many types of cancers, with the cell-surface GRP78 being preferentially present in cancer cells and cancer blood vessel endothelial cells. Isthmin (ISM) is a secreted high-affinity proapoptotic protein ligand of cell-surface GRP78 that suppresses angiogenesis and tumor growth in mice. The C-terminal AMOP (adhesion-associated domain in MUC4 and other proteins) domain of ISM is critical in mediating its interaction with human umbilical vein endothelial cells (HUVECs). In this work, we report novel cyclic peptides harboring the RKD motif in the ISM AMOP domain that function as proapoptotic ligands of cell-surface GRP78. The most potent peptide, BC71, binds to GRP78 and converge to tumor in mice. Intravenous administration of BC71 suppressed xenograft tumor growth in mice as a single agent, with significant reduction in tumor angiogenesis and upsurge in apoptosis. Fluorescent-labeled BC71 accumulates in tumor in mice by targeting cell-surface GRP78. We show that BC71 triggers apoptosis via cell-surface GRP78 and activates caspase-8 and p53 signaling pathways in HUVECs. Using amide hydrogen-deuterium exchange mass spectrometry (HDXMS), we identified that BC71 preferentially binds to ATP-bound GRP78 via amino acid residues 244–257 of GRP78. Hence, BC71 serves as a valuable prototype for further development of peptidomimetic anticancer drugs targeting cell-surface GRP78 as well as PET imaging agents for cancer prognosis.
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影响因子：
11.2
作者：
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通讯作者：
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影响因子：
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作者：
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